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Sample records for rat mammary tumorigenesis

  1. Pregnancy-dependent initiation in tumorigenesis of Wistar rat mammary glands by 60Co-irradiation

    International Nuclear Information System (INIS)

    Inano, Hiroshi; Suzuki, Keiko; Ishii-Ohba, Hiroko; Ikeda, Kiyomi; Wakabayashi, Katsumi

    1991-01-01

    Pregnant Wistar rats received whole body irradiation with 260 cGy γ-rays at days 7, 14 and 20 of pregnancy and then were treated with diethylstilbestrol (DES) for 1 year. The highest incidence (92.9%) for tumorigenesis of mammary glands was observed in the rats irradiated in late pregnancy. Histological examination showed that tumors were classified as fibroadenoma and adenocarcinoma. To determine the reasons for specific induction of mammary tumors by irradiation in late pregnancy, hormone concentrations in serum and estrogen receptors in mammary glands during pregnancy were measured. Concentrations of estradiol, progesterone, 11-deoxycorticosterone and placental lactogen at day 20 were higher than at days 7 and/or 14, but no difference was observed in the concentrations of prolactin and thyroid-stimulating hormone during pregnancy. The estrogen receptor in mammary glands at day 20 was indicated to have the highest affinity and the highest binding capacity during pregnancy. Normal mammary glands at day 20 were suggested to have more abundant epithelial cells in the mammary lobes than those at days 7 and 14. The data suggest that the critical requirements for the initiation of tumorigenesis by γ-rays are dependent upon the differentiated state of mammary glands exposed to various hormones, and that the concentration and persistence of the synthetic estrogen (DES) are necessary for the promotion of tumorigenesis of the irradiated mammary glands. (Author)

  2. Prepubertal exposure to cow's milk reduces susceptibility to carcinogen-induced mammary tumorigenesis in rats

    DEFF Research Database (Denmark)

    Nielsen, Tina Skau; Khan, Galam; Davis, Jennifer

    2011-01-01

    Cow's milk contains high levels of estrogens, progesterone and insulin-like growth factor 1 (IGF-1), all of which are associated with breast cancer. We investigated whether prepubertal milk exposure affects mammary gland development and carcinogenesis in rats. Sprague-Dawley rats were given either...... whole milk or tap water to drink from postnatal day (PND) 14 to PND 35, and thereafter normal tap water. Mammary tumorigenesis was induced by administering 7,12-dimethylbenz[a]anthracene on PND 50. Milk exposure increased circulating E2 levels on PND 25 by 10-fold (p ... opening, which marks puberty onset, by 2.5 days (p milk before puberty exhibited reduced carcinogen-induced mammary carcinogenesis; that is, their tumor latency was longer (p

  3. Multiple susceptibility loci for radiation-induced mammary tumorigenesis in F2[Dahl S x R]-intercross rats.

    Directory of Open Access Journals (Sweden)

    Victoria L Herrera

    Full Text Available Although two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified accounting for 20% of breast cancer genetic risk, identification of other susceptibility genes accounting for 80% risk remains a challenge due to the complex, multi-factorial nature of breast cancer. Complexity derives from multiple genetic determinants, permutations of gene-environment interactions, along with presumptive low-penetrance of breast cancer predisposing genes, and genetic heterogeneity of human populations. As with other complex diseases, dissection of genetic determinants in animal models provides key insight since genetic heterogeneity and environmental factors can be experimentally controlled, thus facilitating the detection of quantitative trait loci (QTL. We therefore, performed the first genome-wide scan for loci contributing to radiation-induced mammary tumorigenesis in female F2-(Dahl S x R-intercross rats. Tumorigenesis was measured as tumor burden index (TBI after induction of rat mammary tumors at forty days of age via ¹²⁷Cs-radiation. We observed a spectrum of tumor latency, size-progression, and pathology from poorly differentiated ductal adenocarcinoma to fibroadenoma, indicating major effects of gene-environment interactions. We identified two mammary tumorigenesis susceptibility quantitative trait loci (Mts-QTLs with significant linkage: Mts-1 on chromosome-9 (LOD-2.98 and Mts-2 on chromosome-1 (LOD-2.61, as well as two Mts-QTLs with suggestive linkage: Mts-3 on chromosome-5 (LOD-1.93 and Mts-4 on chromosome-18 (LOD-1.54. Interestingly, Chr9-Mts-1, Chr5-Mts-3 and Chr18-Mts-4 QTLs are unique to irradiation-induced mammary tumorigenesis, while Chr1-Mts-2 QTL overlaps with a mammary cancer susceptibility QTL (Mcs 3 reported for 7,12-dimethylbenz-[α]antracene (DMBA-induced mammary tumorigenesis in F2[COP x Wistar-Furth]-intercross rats. Altogether, our results suggest at least three distinct susceptibility QTLs for

  4. Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy.

    Science.gov (United States)

    Blakely, Collin M; Stoddard, Alexander J; Belka, George K; Dugan, Katherine D; Notarfrancesco, Kathleen L; Moody, Susan E; D'Cruz, Celina M; Chodosh, Lewis A

    2006-06-15

    Women who have their first child early in life have a substantially lower lifetime risk of breast cancer. The mechanism for this is unknown. Similar to humans, rats exhibit parity-induced protection against mammary tumorigenesis. To explore the basis for this phenomenon, we identified persistent pregnancy-induced changes in mammary gene expression that are tightly associated with protection against tumorigenesis in multiple inbred rat strains. Four inbred rat strains that exhibit marked differences in their intrinsic susceptibilities to carcinogen-induced mammary tumorigenesis were each shown to display significant protection against methylnitrosourea-induced mammary tumorigenesis following treatment with pregnancy levels of estradiol and progesterone. Microarray expression profiling of parous and nulliparous mammary tissue from these four strains yielded a common 70-gene signature. Examination of the genes constituting this signature implicated alterations in transforming growth factor-beta signaling, the extracellular matrix, amphiregulin expression, and the growth hormone/insulin-like growth factor I axis in pregnancy-induced alterations in breast cancer risk. Notably, related molecular changes have been associated with decreased mammographic density, which itself is strongly associated with decreased breast cancer risk. Our findings show that hormone-induced protection against mammary tumorigenesis is widely conserved among divergent rat strains and define a gene expression signature that is tightly correlated with reduced mammary tumor susceptibility as a consequence of a normal developmental event. Given the conservation of this signature, these pathways may contribute to pregnancy-induced protection against breast cancer.

  5. Relationship between histology, development and tumorigenesis of mammary gland in female rat

    Science.gov (United States)

    LÍŠKA, Ján; BRTKO, Július; DUBOVICKÝ, Michal; MACEJOVÁ, Dana; KISSOVÁ, Viktória; POLÁK, Štefan; UJHÁZY, Eduard

    2015-01-01

    The mammary gland is a dynamic organ that undergoes structural and functional changes associated with growth, reproduction, and post-menopausal regression. The postnatal transformations of the epithelium and stromal cells of the mammary gland may contribute to its susceptibility to carcinogenesis. The increased cancer incidence in mammary glands of humans and similarly of rodents in association with their development is believed to be partly explained by proliferative activity together with lesser degree of differentiation, but it is not completely understood how the virgin gland retains its higher susceptibility to carcinogenesis. During its developmental cycle, the mammary gland displays many of the properties associated with breast cancer. An early first full-term pregnancy may have a protective effect. Rodent models are useful for investigating potential breast carcinogens. The purpose of this review is to help recognizing histological appearance of the epithelium and the stroma of the normal mammary gland in rats, and throughout its development in relation to tumorigenic potential. PMID:26424555

  6. Prolactin and aging: X-irradiated and estrogen-induced rat mammary tumorigenesis

    International Nuclear Information System (INIS)

    Ito, A.; Naito, M.; Watanabe, H.; Yokoro, K.

    1984-01-01

    Both sexes of inbred WF rats at either 8 or 28-60 weeks of age were exposed to 200 rad whole-body radiation, 2.5 or 5.0 mg 17 beta-estradiol (E2), or both agents The female rats treated with E2 alone or with both X-rays and E2 at 8 weeks of age showed a high incidence of mammary carcinomas (MCA), a large increase in pituitary weight, and a rise in serum prolactin (PRL) levels. However, the same treatments to males did not induce MCA despite a moderate increase in both pituitary weight and serum PRL. Ovariectomy prior to E2 treatment failed to modify the occurrence of MCA or pituitary tumors. When X-rays and E2 were given to female rats at 28-60 weeks of age, pituitary weight, serum PRL levels, and the incidence of MCA were unaffected. When the E2 pellet was kept for the first 24 weeks and withdrawn during the last 12 weeks, the incidence of MCA, pituitary weight, and serum PRL was low. It was concluded that: 1) the pituitary glands of young female rats were susceptible to E2 treatment but were insensitive in older females, and 2) the occurrence of MCA in female rats appeared to be promoted by elevated PRL levels secreted by E2-induced pituitary tumors. Mammary tissue of male rats was less sensitive to PRL levels in the development of MCA

  7. Trianthema portulacastrum Linn. exerts chemoprevention of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats

    Energy Technology Data Exchange (ETDEWEB)

    Bishayee, Anupam, E-mail: abishayee@auhs.edu [Department of Pharmaceutical Sciences, School of Pharmacy, American University of Health Sciences, Signal Hill, CA 90755 (United States); Mandal, Animesh [Cancer Therapeutics and Chemoprevention Group, Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272 (United States)

    2014-10-15

    Highlights: • Dietary administration of an ethanolic extract of aerial parts of T. portulacastrum (TPE) exhibits a striking chemopreventive effect in an experimentally induced classical animal model of breast cancer. • The mammary tumor-inhibitory effect of TPE could be achieved, at least in part, though intervention of key hallmark capabilities of tumor cells, such as abnormal cell proliferation and evasion of apoptosis. • TPE is capable of diminishing activated canonical Wnt/β-catenin signaling to exhibit antiproliferative, proapoptotic and oncostatic effects during this early-stage mammary carcinoma. • These results coupled with a safety profile of T. portulacastrum may encourage further studies to understand the full potential of this dietary plant for chemoprevention of breast cancer. - Abstract: Due to limited treatment options for advanced-stage metastatic breast cancer, a high priority should be given to develop non-toxic chemopreventive drugs. The value of various natural and dietary agents to reduce the risk of developing breast cancer is well established. Trianthema portulacastrum Linn. (Aizoaceae), a dietary and medicinal plant, has been found to exert antihepatotoxic and antihepatocarcinogenic properties in rodents. This study was initiated to investigate mechanism-based chemopreventive potential of an ethanolic extract of T. portulacastrum (TPE) against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary gland carcinogenesis, an experimental tumor model that closely resembles human breast cancer. Rats had access to a basal diet supplemented with TPE to yield three dietary doses of the extract, i.e., 50, 100 and 200 mg/kg body weight. Following two weeks of TPE treatment, mammary tumorigenesis was initiated by oral administration of DMBA (50 mg/kg body weight). At the end of the study (16 weeks after DMBA exposure), TPE exhibited a striking reduction of DMBA-induced mammary tumor incidence, total tumor burden and average tumor weight

  8. Influence of caffeine and/or coffee consumption on the initiation and promotion phases of 7,12-dimethylbenz(a)anthracene-induced rat mammary gland tumorigenesis.

    Science.gov (United States)

    Welsch, C W; DeHoog, J V; O'Connor, D H

    1988-04-15

    The effect of caffeine and/or coffee consumption (via the drinking water) during the initiation phase and promotion phase of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland tumorigenesis in female Sprague-Dawley rats fed a commercial laboratory animal chow was examined. In the initiation studies, DMBA was administered once at 53-55 days of age; caffeine (100-860 mg/liter of drinking water) and/or coffee (moderate or high dose, sole source of drinking water) treatments were for 32 consecutive days, commencing 29 days prior to DMBA treatment and terminating 3 days after DMBA treatment. In the promotion studies, DMBA was administered once at 54-55 days of age; caffeine and/or coffee treatments were daily from 57-58 days of age to termination of experiments (12-21 weeks after carcinogen treatment). In the initiation studies, either moderate (100-400 mg) or high (860 mg) dose levels of caffeine or moderate to high dose levels of caffeinated coffee significantly (P less than 0.05) reduced mammary carcinoma multiplicity (number of tumors/rat). Consumption of high or moderate dose levels of decaffeinated coffee did not significantly alter mammary carcinoma multiplicity. The addition of caffeine to the moderate dose level of decaffeinated coffee resulted in a significant (P less than 0.05) reduction in mammary carcinoma multiplicity. In the promotion studies, prolonged consumption of moderated dose levels of caffeine or moderate or high dose levels of caffeinated coffee or decaffeinated coffee did not significantly effect mammary carcinoma multiplicity. In the early stages of promotion, however, a significant (p less than 0.05) stimulatory effect of caffeine on mammary carcinoma multiplicity was observed; an effect that was temperate and transitory. In both the initiation and promotion studies caffeine and/or coffee consumption did not significantly affect the incidence of mammary carcinomas (percentage of rats bearing mammary carcinomas) or the mean latency

  9. Influence of caffeine consumption on 7,12-dimethylbenz(a)anthracene-induced mammary gland tumorigenesis in female rats fed a chemically defined diet containing standard and high levels of unsaturated fat.

    Science.gov (United States)

    Welsch, C W; DeHoog, J V

    1988-04-15

    The effect of caffeine (430-500 mg/liter of drinking water) on the initiation and promotion phases of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary gland tumorigenesis in female Sprague-Dawley rats fed a chemically defined diet containing standard (5%) or high (20%) levels of fat (corn oil) was examined. In the initiation studies, caffeine and the standard or high fat diet treatments were provided for 34 days, from 24-29 days of age to 58-63 days of age. Three days prior to termination of caffeine-fat diet treatments, each rat received a single dose of DMBA. In the promotion studies, caffeine and the standard or high fat diets were provided commencing 3 days after a single dose of DMBA (at 56-61 days of age) and until termination of the study. Caffeine consumption, during the initiation phase significantly (P less than 0.05) reduced mammary carcinoma multiplicity (number of tumors/rat), in rats fed either a standard or high fat diet. In the promotion studies, prolonged consumption of caffeine in rats fed either a standard or high fat diet did not significantly effect mammary carcinoma multiplicity. In the early stages of promotion, an apparent increase in mammary carcinoma multiplicity was observed; this increase in mammary carcinoma multiplicity did not, however, reach the 5% level of statistical probability. When caffeine was administered during both the initiation and promotion phases, no significant effect on mammary carcinoma multiplicity was observed. Treatment of rats during the initiation or promotion phases with caffeinated coffee (via drinking water) mimicked the mammary tumor modulating activities of caffeine. Decaffeinated coffee consumption did not effect either the initiation or promotion phases of this tumorigenic process. In both the initiation and promotion studies, caffeine and/or coffee consumption did not significantly affect the incidence of mammary carcinomas (percentage of rats bearing mammary carcinomas) or the mean latency period of

  10. Naturally-occurring estradiol-17β-fatty acid esters, but not estradiol-17β, preferentially induce mammary tumorigenesis in female rats: Implications for an important role in human breast cancer

    International Nuclear Information System (INIS)

    Mills, Laura H.; Yu Jina; Xu Xiaomeng; Lee, Anthony J.; Zhu Baoting

    2008-01-01

    Because mammary glands are surrounded by adipose tissues, we hypothesize that the ultra-lipophilic endogenous estrogen-17β-fatty acid esters may have preferential hormonal and carcinogenic effects in mammary tissues compared to other target organs (such as the uterus and pituitary). This hypothesis is tested in the present study. We found that all 46 rats implanted with an estradiol-17β pellet developed large pituitary tumors (average weight = 251 ±103 mg) and had to be terminated early, but only 48% of them developed mammary tumors. In addition, approximately one-fourth of them developed a huge uterus. In the 26 animals implanted with a mixture containing estradiol-17β-stearate and estradiol-17β-palmitate (two representative estradiol-17β-fatty acid esters) or in the 29 animals implanted with estradiol-17β-stearate alone (in the same molar dose as estradiol-17β), 73% and 79%, respectively, of them developed mammary tumors, whereas only 3 or 2 animals, respectively, had to be terminated early due to the presence of a large pituitary tumor. Both tumorous and normal mammary tissues contained much higher levels of estrogen esterase than other tissues, which catalyzes the releases of bioactive estrogens from their fatty acid esters. In conclusion, while estradiol-17β is much stronger in inducing pituitary tumor (100% incidence) than mammary tumor, estradiol-17β-fatty acid esters have a higher efficacy than estradiol-17β in inducing mammary tumor and yet it only has little ability to induce uterine out-growth and pituitary tumorigenesis. This study establishes the endogenous estrogen-17β-fatty acid esters as preferential inducers of mammary tumorigenesis

  11. Effects of maternal exposure to cow´s milk high or low in isoflavones on carcinogen-induced mammary tumorigenesis among rat offspring

    DEFF Research Database (Denmark)

    Nielsen, Tina Skau; Purup, Stig; Warri, A

    2011-01-01

    We investigated whether maternal exposure during pregnancy to cow's milk containing endogenous estrogens and insulin like growth factor 1 (IGF-1) and either high or low levels of isoflavones from dietary legumes (HIM and LIM, respectively) affected carcinogen-induced mammary carcinogenesis....... No differences in maternal serum estradiol (P = 0.19) and IGF-1 levels (P = 0.15) at GD 19 or birth weight among the milk and water groups were seen, but estradiol, and IGF-1 levels and birth weight were numerically higher in the LIM than in the HIM group. Puberty onset occurred earlier in the LIM offspring than...... in controls (P = 0.03). Although the high isoflavone content seemed to prevent the effect on circulating estradiol and IGF-1 levels and advanced puberty onset seen in the LIM group, HIM increased DMBA-DNA adducts in the mammary gland and tended to increase mammary tumorigenesis. In contrast, offspring exposed...

  12. STAT signaling in mammary gland differentiation, cell survival and tumorigenesis.

    Science.gov (United States)

    Haricharan, S; Li, Y

    2014-01-25

    The mammary gland is a unique organ that undergoes extensive and profound changes during puberty, menstruation, pregnancy, lactation and involution. The changes that take place during puberty involve large-scale proliferation and invasion of the fat-pad. During pregnancy and lactation, the mammary cells are exposed to signaling pathways that inhibit apoptosis, induce proliferation and invoke terminal differentiation. Finally, during involution the mammary gland is exposed to milk stasis, programmed cell death and stromal reorganization to clear the differentiated milk-producing cells. Not surprisingly, the signaling pathways responsible for bringing about these changes in breast cells are often subverted during the process of tumorigenesis. The STAT family of proteins is involved in every stage of mammary gland development, and is also frequently implicated in breast tumorigenesis. While the roles of STAT3 and STAT5 during mammary gland development and tumorigenesis are well studied, others members, e.g. STAT1 and STAT6, have only recently been observed to play a role in mammary gland biology. Continued investigation into the STAT protein network in the mammary gland will likely yield new biomarkers and risk factors for breast cancer, and may also lead to novel prophylactic or therapeutic strategies against breast cancer. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  13. Progenitor Cell Fate Decisions in Mammary Tumorigenesis

    Science.gov (United States)

    2013-03-01

    effects of co-transplantation of these populations. Understanding the relationships between normal and transformed mammary epithelial cells has... effect of E2 against double-strand break damage was dependent on ER expression. NBS1 mediated the E2 protective effects against ionizing radiation...transfected with 2 Jeg of pGL3 lucif - erase reporter vector containing S’ flanking constructs of the NBSl promoter, ellon 1 and intron 1 (-360/+1076

  14. The Role of Phosphatidylinositol 3' -OH Kinase Signaling in Mammary Tumorigenesis

    National Research Council Canada - National Science Library

    Hutchinson, John

    2002-01-01

    ...) and its downstream target Akt kinase in the induction of mammary tumors. To assess the role of Akt in mammary development and tumorigenesis, we generated transgenic mice that express an activated Akt (Akt-DD...

  15. The Role of Phosphatidylinositol 3' -OH Kinase Signaling in Mammary Tumorigenesis

    National Research Council Canada - National Science Library

    Hutchinson, John

    2001-01-01

    ...) and its downstream targets such as the Akt kinase in the induction of mammary tumors. To assess the role of Akt in mammary development and tumorigenesis, we have generated transgenic mice that express an activated Akt (Akt-DD...

  16. Synergistic effect of lycopene and tocopherol against oxidative stress and mammary tumorigenesis induced by 7,12-dimethyl[a]benzanthracene in female rats.

    Science.gov (United States)

    Al-Malki, Abdulrahman L; Moselhy, Said S; Refai, Mohammed Y

    2012-07-01

    Breast cancer is one of the most serious problems in oncology. We investigated the antitumor potential of lycopene (Lyco) alone or combined with tocopherol (Lyco + Toco) for 90 days against a single oral dose of (50 mg/kg body weight) 7,12-dimethyl[a]benzanthracene (DMBA)-induced oxidative stress and mammary carcinogenesis in female rats. The treatment protocol started from the day immediately after DMBA administration. Results obtained indicated that there was a significant elevation in the levels of malondialdehyde (MDA) and nitric oxide (NO) in serum and breast tissues of DMBA-injected rats. The combined treatment (Lyco + Toco) group showed a potential reduction of these parameters more than Lyco alone group. The activities of superoxide dismutase, catalase, and glutathione peroxidase were found to be significantly higher when compared to rats treated with Lyco alone. In DMBA group, a positive significant correlation between NO and MDA (r = 0.92) was observed. Histopathological examination revealed the formation of tumor and angiogenesis in DMBA-induced rats and these abnormal changes were ameliorated by combined treatment with Lyco + Toco. In conclusion, these results suggested that supplementation of diet with Lyco and Toco provided antioxidant defense, with strong chemopreventive activity against DMBA-induced mammary tumors.

  17. The Role of DN-GSK3beta in Mammary Tumorigenesis

    Science.gov (United States)

    2006-07-01

    factors and dramatically increases their transcriptional activity. Genes up- regulated by TCF/LEF include embryologic genes, such as siamois and engrailed...and increased apoptosis occurs in the mammary epithelia (33). Overexpression of the regulator CK2a also promotes mammary tumorigenesis (34). In this

  18. Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-γ

    Science.gov (United States)

    Lee, Hong Jin; Ju, Jihyeung; Paul, Shiby; So, Jae-Young; DeCastro, Andrew; Smolarek, Amanda; Lee, Mao-Jung; Yang, Chung S.; Newmark, Harold L.; Suh, Nanjoo

    2009-01-01

    Purpose Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of α-tocopherol (vitamin E) have been studied for decades, recent intervention studies with α-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of 4 isoforms, α, β, γ, and δ variants, and recent attention is being made to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in γ- and δ-tocopherols against mammary tumorigenesis. Experimental Design Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in γ- and δ-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells. Results Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3 and peroxisome proliferator activated receptor-γ (PPAR-γ), and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that γ- and δ-tocopherols, but not α-tocopherol, activated PPAR-γ and antagonized estrogen action in breast cancer. Conclusion The results suggest that γ- and δ-tocopherols may be effective agents for the prevention of breast cancer. PMID:19509159

  19. Stromal and Epithelial Caveolin-1 Both Confer a Protective Effect Against Mammary Hyperplasia and Tumorigenesis

    Science.gov (United States)

    Williams, Terence M.; Sotgia, Federica; Lee, Hyangkyu; Hassan, Ghada; Di Vizio, Dolores; Bonuccelli, Gloria; Capozza, Franco; Mercier, Isabelle; Rui, Hallgeir; Pestell, Richard G.; Lisanti, Michael P.

    2006-01-01

    Here, we investigate the role of caveolin-1 (Cav-1) in breast cancer onset and progression, with a focus on epithelial-stromal interactions, ie, the tumor microenvironment. Cav-1 is highly expressed in adipocytes and is abundant in mammary fat pads (stroma), but it remains unknown whether loss of Cav-1 within mammary stromal cells affects the differentiated state of mammary epithelia via paracrine signaling. To address this issue, we characterized the development of the mammary ductal system in Cav-1−/− mice and performed a series of mammary transplant studies, using both wild-type and Cav-1−/− mammary fat pads. Cav-1−/− mammary epithelia were hyperproliferative in vivo, with dramatic increases in terminal end bud area and mammary ductal thickness as well as increases in bromodeoxyuridine incorporation, extracellular signal-regulated kinase-1/2 hyperactivation, and up-regulation of STAT5a and cyclin D1. Consistent with these findings, loss of Cav-1 dramatically exacerbated mammary lobulo-alveolar hyperplasia in cyclin D1 Tg mice, whereas overexpression of Cav-1 caused reversion of this phenotype. Most importantly, Cav-1−/− mammary stromal cells (fat pads) promoted the growth of both normal mammary ductal epithelia and mammary tumor cells. Thus, Cav-1 expression in both epithelial and stromal cells provides a protective effect against mammary hyperplasia as well as mammary tumorigenesis. PMID:17071600

  20. Inducible transgenics. New lessons on events governing the induction and commitment in mammary tumorigenesis

    International Nuclear Information System (INIS)

    Hulit, James; Di Vizio, Dolores; Pestell, Richard G

    2001-01-01

    Breast cancer arises from multiple genetic events that together contribute to the established, irreversible malignant phenotype. The development of inducible tissue-specific transgenics has allowed a careful dissection of the events required for induction and subsequent maintenance of tumorigenesis. Mammary gland targeted expression of oncogenic Ras or c-Myc is sufficient for the induction of mammary gland tumorigenesis in the rodent, and when overexpressed together the rate of tumor onset is substantially enhanced. In an exciting recent finding, D'Cruz et al discovered tetracycline-regulated c-Myc overexpression in the mammary gland induced invasive mammary tumors that regressed upon withdrawal of c-Myc expression. Almost one-half of the c-Myc-induced tumors harbored K-ras or N-ras gene point mutations, correlating with tumor persistence on withdrawal of c-Myc transgene expression. These findings suggest maintenance of tumorigenesis may involve a second mutation within the Ras pathway

  1. STAT signaling in mammary gland differentiation, cell survival and tumorigenesis

    OpenAIRE

    Haricharan, S; Li, Y

    2013-01-01

    The mammary gland is a unique organ that undergoes extensive and profound changes during puberty, menstruation, pregnancy, lactation and involution. The changes that take place during puberty involve large-scale proliferation and invasion of the fat-pad. During pregnancy and lactation, the mammary cells are exposed to signaling pathways that inhibit apoptosis, induce proliferation and invoke terminal differentiation. Finally, during involution the mammary gland is exposed to milk stasis, prog...

  2. Mammary tumorigenesis in APCmin/+ mice is enhanced by X-irradiation with a characteristic age dependence

    International Nuclear Information System (INIS)

    Tatsuhiko, Imaoka; Mayumi, Nishimura; Shizuko, Kakinuma; Yoshiya, Shimada; Mieko, Okamoto

    2006-01-01

    The ApcM min/+ (Min) mouse is a genetically predisposed model of both intestinal and mammary tumorigenesis. We investigated age-related changes in the susceptibility of mice (before, during and after puberty) to radiation-induced mammary tumorigenesis using this model. Female Min and wild-type mice having the C57BL/6J background were irradiated with 2 Gy of X-rays at 2, 5, 7 and 10 weeks and sacrificed at 18 weeks of age. Min mice irradiated at 7 to 10 weeks of age (after puberty) developed mammary tumors with squamous metaplasia, whereas their wild-type litter-mates did not. Interestingly, irradiation of Min mice at 2 to 5 weeks (before and during puberty, respectively) did not induce mammary tumors but rather cystic nodules with metaplasia. The mammary tumors exhibited increased nuclear beta-catenin protein and loss of the wild-type Apc allele. Our results show that susceptibility to radiation-induced mammary tumorigenesis increases after puberty in Min mice, suggesting that the tumorigenic effect of ionizing radiation targets the lobular-alveolar progenitor cells, which increase in number with age and are controlled by beta-catenin signaling. (author)

  3. Cdk2-Null Mice Are Resistant to ErbB-2-Induced Mammary Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Dipankar Ray

    2011-05-01

    Full Text Available The concept of targeting G1 cyclin-dependent kinases (CDKs in breast cancer treatments is supported by the fact that the genetic ablation of Cdk4 had minimal impacts on normal cell proliferation in majority of cell types, resulting in near-normal mouse development, whereas such loss of Cdk4 completely abrogated ErbB-2/neu-induced mammary tumorigenesis in mice. In most human breast cancer tissues, another G1-regulatory CDK, CDK2, is also hyperactivated by various mechanisms and is believed to be an important therapeutic target. In this report, we provide genetic evidence that CDK2 is essential for proliferation and oncogenesis of murine mammary epithelial cells. We observed that 87% of Cdk2-null mice were protected from ErbB-2-induced mammary tumorigenesis. Mouse embryonic fibroblasts isolated from Cdk2-null mouse showed resistance to various oncogene-induced transformation. Previously, we have reported that hemizygous loss of Cdc25A, the major activator of CDK2, can also protect mice from ErbB-2-induced mammary tumorigenesis [Cancer Res (2007 67(14: 6605–11]. Thus, we propose that CDC25A-CDK2 pathway is critical for the oncogenic action of ErbB-2 in mammary epithelial cells, in a manner similar to Cyclin D1/CDK4 pathway.

  4. Modifying factors in rat mammary gland carcinogenesis

    International Nuclear Information System (INIS)

    Shellabarger, C.J.

    1975-01-01

    The spontaneous incidence of mammary adenocarcinomas and mammary fibroadenomas in rats was found to be related to the strain of rat studied. Strains of rats that are sensitive to chemical carcinogens in regard to induced mammary neoplasia tend to be the same strains of rats that are sensitive to radiation. Methylcholantrene (MCA) and x-rays appeared to act in an additive fashion on the induction of mammary adenocarcinomas when they were given together. Lactating and older rats lose responsiveness to chemical carcinogens but do not lose responsiveness to radiation. Radiation appears to act in a scopal fashion in the induction of mammary neoplasia. Mammary neoplasia induction was not changed when low LET radiation was split into 2 equal fractions and high LET radiation was more effective than low LET radiation in inducing mammary neoplasia. It is suggested that DMBA can act as an initiator for the induction of mammary adenocarcinomas, that phorbol can act as a promotor, and that viruses may induce mammary neoplasia. Diethylstilbestrol (DES) and radiation appeared to act synergistically in the induction of mammary adenocarcinomas in one strain of rat but not in another strain. (U.S.)

  5. The Role of Src in Mammary Epithelial Tumorigenesis

    National Research Council Canada - National Science Library

    Kusdra, Leonard

    2007-01-01

    ...') similar to the physiological lobular-aveoli structures found in the mammary tissue. Additionally, more invasive carcinoma cells (MDA-MB-231 cells) whereby Src signaling was pharmacologically or genetically inhibited were unable to form actin-rich invasive structures in 3D-rBM culture.

  6. DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis.

    Science.gov (United States)

    Pathania, Rajneesh; Ramachandran, Sabarish; Elangovan, Selvakumar; Padia, Ravi; Yang, Pengyi; Cinghu, Senthilkumar; Veeranan-Karmegam, Rajalakshmi; Arjunan, Pachiappan; Gnana-Prakasam, Jaya P; Sadanand, Fulzele; Pei, Lirong; Chang, Chang-Sheng; Choi, Jeong-Hyeon; Shi, Huidong; Manicassamy, Santhakumar; Prasad, Puttur D; Sharma, Suash; Ganapathy, Vadivel; Jothi, Raja; Thangaraju, Muthusamy

    2015-04-24

    Mammary stem/progenitor cells (MaSCs) maintain self-renewal of the mammary epithelium during puberty and pregnancy. DNA methylation provides a potential epigenetic mechanism for maintaining cellular memory during self-renewal. Although DNA methyltransferases (DNMTs) are dispensable for embryonic stem cell maintenance, their role in maintaining MaSCs and cancer stem cells (CSCs) in constantly replenishing mammary epithelium is unclear. Here we show that DNMT1 is indispensable for MaSC maintenance. Furthermore, we find that DNMT1 expression is elevated in mammary tumours, and mammary gland-specific DNMT1 deletion protects mice from mammary tumorigenesis by limiting the CSC pool. Through genome-scale methylation studies, we identify ISL1 as a direct DNMT1 target, hypermethylated and downregulated in mammary tumours and CSCs. DNMT inhibition or ISL1 expression in breast cancer cells limits CSC population. Altogether, our studies uncover an essential role for DNMT1 in MaSC and CSC maintenance and identify DNMT1-ISL1 axis as a potential therapeutic target for breast cancer treatment.

  7. Podoplanin regulates mammary stem cell function and tumorigenesis by potentiating Wnt/β-catenin signaling.

    Science.gov (United States)

    Bresson, Laura; Faraldo, Marisa M; Di-Cicco, Amandine; Quintanilla, Miguel; Glukhova, Marina A; Deugnier, Marie-Ange

    2018-02-21

    Stem cells (SCs) drive mammary development, giving rise postnatally to an epithelial bilayer composed of luminal and basal myoepithelial cells. Dysregulation of SCs is thought to be at the origin of certain breast cancers; however, the molecular identity of SCs and the factors regulating their function remain poorly defined. We identified the transmembrane protein podoplanin (Pdpn) as a specific marker of the basal compartment, including multipotent SCs, and found Pdpn localized at the basal-luminal interface. Embryonic deletion of Pdpn targeted to basal cells diminished basal and luminal SC activity and affected the expression of several Wnt/β-catenin signaling components in basal cells. Moreover, Pdpn loss attenuated mammary tumor formation in a mouse model of β-catenin-induced breast cancer, limiting tumor-initiating cell expansion and promoting molecular features associated with mesenchymal-to-epithelial cell transition. In line with the loss-of-function data, we demonstrated that mechanistically Pdpn enhances Wnt/β-catenin signaling in mammary basal cells. Overall, this study uncovers a role for Pdpn in mammary SC function and, importantly, identifies Pdpn as a new regulator of Wnt/β-catenin signaling, a key pathway in mammary development and tumorigenesis. © 2018. Published by The Company of Biologists Ltd.

  8. Genetic susceptibility to mammary carcinogenesis in rats

    Energy Technology Data Exchange (ETDEWEB)

    Kamiya, Kenji; Nitta, Yumiko [Hiroshima Univ. (Japan). Research Inst. for Radiation Biology and Medicine

    1999-06-01

    The Copenhagen (COP) rat strain has previously been shown to be genetically resistant to chemical induction of breast cancer, while Wistar/Furth (WF) and Fischer 344 (F344) animals are relatively susceptible. We have compared the carcinogenic response of these three strains of rats to N-methyl-N-nitrosourea (MNU) with that to {sup 60}Co gamma rays. High incidences of mammary carcinomas were induced by MNU in the F344 and WF rats (100%), whereas the COP strain proved resistant (11.8%). In contrast, radiation-induced mammary carcinomas in COP rats developed in a similar incidence (37.0%) to those in the F344 (22.6%) and WF (26.9%) strains. The low incidence of papillary carcinomas in MNU-treated COP rats appeared to be directly related to the COP genetic resistance controlled by the Mcs genes. Ionizing radiation did, however, induce papillary carcinomas in all the three strains of rats. These carcinomas were more differentiated than MNU-induced cancers with regard to the two mammary differentiation markers, rat milk fat globule membrane (R-MFGM) and {alpha}-smooth muscle actin ({alpha}-SMA). Furthermore, ionizing radiation but not MNU induced mammary adenomas in all three strains, especially in COP rats. Such adenomas had differentiation marker profiles similar to these of carcinomas induced by {sup 60}Co gamma rays. When transplanted into syngenic hosts, growth of adenomas was 17 {beta}-estradiol (E{sub 2})-dependent and they progressed to carcinomas. Furthermore, one microcarcinoma was observed to develop from adenoma tissue in a radiation-exposed COP rat. The findings suggest that radiation and chemical carcinogens are likely to induce mammary cancers through different pathways or from different cell populations. The induction of relatively high incidences of mammary carcinomas and adenomas by radiation in COP rats may correlate with the genetically modulated and highly differentiated physiological status of their mammary glands. (author)

  9. Influence of prevastein (R), an isoflavone-rich soy product, on mammary gland development and Tumorigenesis in Tg.NK (MMTV/c-neu) mice

    DEFF Research Database (Denmark)

    Thomsen, Anni R.; Mortensen, Alicja; Breinholt, Vibeke

    2005-01-01

    We investigated spontaneous mammary tumor development and mammary gland morphogenesis in female Tg.NK mice postnatally exposed to dietary soy isoflavones (0, 11, 39, and 130 mg aglycones/kg diet) added to a Western-style diet. Instead of preventing mammary tumorigenesis, the highest dose of isofl......We investigated spontaneous mammary tumor development and mammary gland morphogenesis in female Tg.NK mice postnatally exposed to dietary soy isoflavones (0, 11, 39, and 130 mg aglycones/kg diet) added to a Western-style diet. Instead of preventing mammary tumorigenesis, the highest dose...

  10. Mammary tumorigenesis in APC{sup min/+} mice is enhanced by X-irradiation with a characteristic age dependence

    Energy Technology Data Exchange (ETDEWEB)

    Tatsuhiko, Imaoka; Mayumi, Nishimura; Shizuko, Kakinuma; Yoshiya, Shimada [National Institute of Radiological Sciences, Experimental Radiobiology for Children' s Health Research Group, Research, Center for Radiation Protection (Japan); Mieko, Okamoto [Tokyo Metropolitan Institute of Medical Science (Japan)

    2006-07-01

    The ApcM{sup min/+} (Min) mouse is a genetically predisposed model of both intestinal and mammary tumorigenesis. We investigated age-related changes in the susceptibility of mice (before, during and after puberty) to radiation-induced mammary tumorigenesis using this model. Female Min and wild-type mice having the C57BL/6J background were irradiated with 2 Gy of X-rays at 2, 5, 7 and 10 weeks and sacrificed at 18 weeks of age. Min mice irradiated at 7 to 10 weeks of age (after puberty) developed mammary tumors with squamous metaplasia, whereas their wild-type litter-mates did not. Interestingly, irradiation of Min mice at 2 to 5 weeks (before and during puberty, respectively) did not induce mammary tumors but rather cystic nodules with metaplasia. The mammary tumors exhibited increased nuclear beta-catenin protein and loss of the wild-type Apc allele. Our results show that susceptibility to radiation-induced mammary tumorigenesis increases after puberty in Min mice, suggesting that the tumorigenic effect of ionizing radiation targets the lobular-alveolar progenitor cells, which increase in number with age and are controlled by beta-catenin signaling. (author)

  11. In vivo fluorescence imaging reveals the promotion of mammary tumorigenesis by mesenchymal stromal cells.

    Directory of Open Access Journals (Sweden)

    Chien-Chih Ke

    Full Text Available Mesenchymal stromal cells (MSCs are multipotent adult stem cells which are recruited to the tumor microenvironment (TME and influence tumor progression through multiple mechanisms. In this study, we examined the effects of MSCs on the tunmorigenic capacity of 4T1 murine mammary cancer cells. It was found that MSC-conditioned medium increased the proliferation, migration, and efficiency of mammosphere formation of 4T1 cells in vitro. When co-injected with MSCs into the mouse mammary fat pad, 4T1 cells showed enhanced tumor growth and generated increased spontaneous lung metastasis. Using in vivo fluorescence color-coded imaging, the interaction between GFP-expressing MSCs and RFP-expressing 4T1 cells was monitored. As few as five 4T1 cells could give rise to tumor formation when co-injected with MSCs into the mouse mammary fat pad, but no tumor was formed when five or ten 4T1 cells were implanted alone. The elevation of tumorigenic potential was further supported by gene expression analysis, which showed that when 4T1 cells were in contact with MSCs, several oncogenes, cancer markers, and tumor promoters were upregulated. Moreover, in vivo longitudinal fluorescence imaging of tumorigenesis revealed that MSCs created a vascularized environment which enhances the ability of 4T1 cells to colonize and proliferate. In conclusion, this study demonstrates that the promotion of mammary cancer progression by MSCs was achieved through the generation of a cancer-enhancing microenvironment to increase tumorigenic potential. These findings also suggest the potential risk of enhancing tumor progression in clinical cell therapy using MSCs. Attention has to be paid to patients with high risk of breast cancer when considering cell therapy with MSCs.

  12. Chemoprevention of Rat Mammary Carcinogenesis by Apiaceae Spices

    Directory of Open Access Journals (Sweden)

    Farrukh Aqil

    2017-02-01

    Full Text Available Scientific evidence suggests that many herbs and spices have medicinal properties that alleviate symptoms or prevent disease. In this study, we examined the chemopreventive effects of the Apiaceae spices, anise, caraway, and celery seeds against 17β-estrogen (E2-mediated mammary tumorigenesis in an ACI (August-Copenhagen Irish rat model. Female ACI rats were given either control diet (AIN 93M or diet supplemented with 7.5% (w/w of anise, caraway, or celery seed powder. Two weeks later, one half of the animals in each group received subcutaneous silastic implants of E2. Diet intake and body weight were recorded weekly, and animals were euthanized after 3 and 12 weeks. E2-treatment showed significantly (2.1- and 3.4-fold enhanced growth of pituitary gland at 3 and 12 weeks, respectively. All test spices significantly offset the pituitary growth by 12 weeks, except celery which was effective as early as three weeks. Immunohistochemical analysis for proliferative cell nuclear antigen (PCNA in mammary tissues showed significant reduction in E2-mediated mammary cell proliferation. Test spices reduced the circulating levels of both E2 and prolactin at three weeks. This protection was more pronounced at 12 weeks, with celery eliciting the highest effect. RT-PCR and western blot analysis were performed to determine the potential molecular targets of the spices. Anise and caraway diets significantly offset estrogen-mediated overexpression of both cyclin D1 and estrogen receptor α (ERα. The effect of anise was modest. Likewise, expression of CYP1B1 and CYP1A1 was inhibited by all test spices. Based on short-term molecular markers, caraway was selected over other spices based on its enhanced effect on estrogen-associated pathway. Therefore, a tumor-end point study in ACI rats was conducted with dietary caraway. Tumor palpation from 12 weeks onwards revealed tumor latency of 29 days in caraway-treated animals compared with first tumor appearance at 92

  13. Chemoprevention of Rat Mammary Carcinogenesis by Apiaceae Spices.

    Science.gov (United States)

    Aqil, Farrukh; Jeyabalan, Jeyaprakash; Munagala, Radha; Ravoori, Srivani; Vadhanam, Manicka V; Schultz, David J; Gupta, Ramesh C

    2017-02-16

    Scientific evidence suggests that many herbs and spices have medicinal properties that alleviate symptoms or prevent disease. In this study, we examined the chemopreventive effects of the Apiaceae spices, anise, caraway, and celery seeds against 17β-estrogen (E2)-mediated mammary tumorigenesis in an ACI (August-Copenhagen Irish) rat model. Female ACI rats were given either control diet (AIN 93M) or diet supplemented with 7.5% ( w / w ) of anise, caraway, or celery seed powder. Two weeks later, one half of the animals in each group received subcutaneous silastic implants of E2. Diet intake and body weight were recorded weekly, and animals were euthanized after 3 and 12 weeks. E2-treatment showed significantly (2.1- and 3.4-fold) enhanced growth of pituitary gland at 3 and 12 weeks, respectively. All test spices significantly offset the pituitary growth by 12 weeks, except celery which was effective as early as three weeks. Immunohistochemical analysis for proliferative cell nuclear antigen (PCNA) in mammary tissues showed significant reduction in E2-mediated mammary cell proliferation. Test spices reduced the circulating levels of both E2 and prolactin at three weeks. This protection was more pronounced at 12 weeks, with celery eliciting the highest effect. RT-PCR and western blot analysis were performed to determine the potential molecular targets of the spices. Anise and caraway diets significantly offset estrogen-mediated overexpression of both cyclin D1 and estrogen receptor α (ERα). The effect of anise was modest. Likewise, expression of CYP1B1 and CYP1A1 was inhibited by all test spices. Based on short-term molecular markers, caraway was selected over other spices based on its enhanced effect on estrogen-associated pathway. Therefore, a tumor-end point study in ACI rats was conducted with dietary caraway. Tumor palpation from 12 weeks onwards revealed tumor latency of 29 days in caraway-treated animals compared with first tumor appearance at 92 days in

  14. Exploring the gain of function contribution of AKT to mammary tumorigenesis in mouse models.

    Directory of Open Access Journals (Sweden)

    Carmen Blanco-Aparicio

    Full Text Available Elevated expression of AKT has been noted in a significant percentage of primary human breast cancers, mainly as a consequence of the PTEN/PI3K pathway deregulation. To investigate the mechanistic basis of the AKT gain of function-dependent mechanisms of breast tumorigenesis, we explored the phenotype induced by activated AKT transgenes in a quantitative manner. We generated several transgenic mice lines expressing different levels of constitutively active AKT in the mammary gland. We thoroughly analyzed the preneoplastic and neoplastic mammary lesions of these mice and correlated the process of tumorigenesis to AKT levels. Finally, we analyzed the impact that a possible senescent checkpoint might have in the tumor promotion inhibition observed, crossing these lines to mammary specific p53(R172H mutant expression, and to p27 knock-out mice. We analyzed the benign, premalignant and malignant lesions extensively by pathology and at molecular level analysing the expression of proteins involved in the PI3K/AKT pathway and in cellular senescence. Our findings revealed an increased preneoplastic phenotype depending upon AKT signaling which was not altered by p27 or p53 loss. However, p53 inactivation by R172H point mutation combined with myrAKT transgenic expression significantly increased the percentage and size of mammary carcinoma observed, but was not sufficient to promote full penetrance of the tumorigenic phenotype. Molecular analysis suggest that tumors from double myrAKT;p53(R172H mice result from acceleration of initiated p53(R172H tumors and not from bypass of AKT-induced oncogenic senescence. Our work suggests that tumors are not the consequence of the bypass of senescence in MIN. We also show that AKT-induced oncogenic senescence is dependent of pRb but not of p53. Finally, our work also suggests that the cooperation observed between mutant p53 and activated AKT is due to AKT-induced acceleration of mutant p53-induced tumors. Finally, our

  15. Charles River Sprague Dawley rats lack early age-dependent susceptibility to DMBA-induced mammary carcinogenesis.

    Science.gov (United States)

    Gear, R B; Yan, M; Schneider, J; Succop, P; Heffelfinger, S C; Clegg, D J

    2007-10-04

    Developmental stages of mammary glands influence their susceptibility to initiating events related to carcinogenesis. The "window of susceptibility" to mammary carcinogenesis is classically defined as the time in early puberty when the mammary gland morphology is most sensitive to initiation events. Administration of the polyaromatic hydrocarbon, 7,12-dimethylbenz(a)anthracene (DMBA), in a single oral dose yields maximal mammary tumor formation when administered in this "window". We examined the DMBA treated mammary glands, precursor lesions, and morphology of the uninvolved mammary epithelium for the first 100 days of life for Charles River Sprague Dawley CD(R) IGS. Our goal was to determine the DMBA dose at which 50% of the rats (IC50) developed carcinoma in situ (CIS) within three months of dosing. Here we demonstrate, rather than the classical U-shaped dose curve in which there is maximum sensitivity for DMBA at 50 days, there is an increasing degree of sensitivity with age in the CD(R) IGS rat. Additionally, we report that vehicle-treated animals developed mammary CIS without any known initiator, and 100 day virgin animals demonstrated lactational changes, independent of DMBA exposure or dose. Lastly, we demonstrate this strain of virgin female rats has elevated pituitary prolactin immunoreactivity independent of the level of mammary differentiation. We conclude this strain of Charles River Sprague Dawley rats has prolactin-induced pituitary stimulation, and therefore, the window of susceptibility for mammary tumorigenesis is absent.

  16. A targeted constitutive mutation in the APC tumor suppressor gene underlies mammary but not intestinal tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Claudia Gaspar

    2009-07-01

    Full Text Available Germline mutations in the adenomatous polyposis coli (APC gene are responsible for familial adenomatous polyposis (FAP, an autosomal dominant hereditary predisposition to the development of multiple colorectal adenomas and of a broad spectrum of extra-intestinal tumors. Moreover, somatic APC mutations play a rate-limiting and initiating role in the majority of sporadic colorectal cancers. Notwithstanding its multifunctional nature, the main tumor suppressing activity of the APC gene resides in its ability to regulate Wnt/beta-catenin signaling. Notably, genotype-phenotype correlations have been established at the APC gene between the length and stability of the truncated proteins encoded by different mutant alleles, the corresponding levels of Wnt/beta-catenin signaling activity they encode for, and the incidence and distribution of intestinal and extra-intestinal tumors. Here, we report a novel mouse model, Apc1572T, obtained by targeting a truncated mutation at codon 1572 in the endogenous Apc gene. This hypomorphic mutant allele results in intermediate levels of Wnt/beta-catenin signaling activation when compared with other Apc mutations associated with multifocal intestinal tumors. Notwithstanding the constitutive nature of the mutation, Apc(+/1572T mice have no predisposition to intestinal cancer but develop multifocal mammary adenocarcinomas and subsequent pulmonary metastases in both genders. The histology of the Apc1572T primary mammary tumours is highly heterogeneous with luminal, myoepithelial, and squamous lineages and is reminiscent of metaplastic carcinoma of the breast in humans. The striking phenotype of Apc(+/1572T mice suggests that specific dosages of Wnt/beta-catenin signaling activity differentially affect tissue homeostasis and initiate tumorigenesis in an organ-specific fashion.

  17. A moderate elevation of circulating levels of IGF-I does not alter ErbB2 induced mammary tumorigenesis

    International Nuclear Information System (INIS)

    Dearth, Robert K; Kuiatse, Isere; Wang, Yu-Fen; Liao, Lan; Hilsenbeck, Susan G; Brown, Powel H; Xu, Jianming; Lee, Adrian V

    2011-01-01

    Epidemiological evidence suggests that moderately elevated levels of circulating insulin-like growth factor-I (IGF-I) are associated with increased risk of breast cancer in women. How circulating IGF-I may promote breast cancer incidence is unknown, however, increased IGF-I signaling is linked to trastuzumab resistance in ErbB2 positive breast cancer. Few models have directly examined the effect of moderately high levels of circulating IGF-I on breast cancer initiation and progression. The purpose of this study was to assess the ability of circulating IGF-I to independently initiate mammary tumorigenesis and/or accelerate the progression of ErbB2 mediated mammary tumor growth. We crossed heterozygous TTR-IGF-I mice with heterozygous MMTV-ErbB2 mice to generate 4 different genotypes: TTR-IGF-I/MMTV-ErbB2 (bigenic), TTR-IGF-I only, MMTV-ErbB2 only, and wild type (wt). Virgin females were palpated twice a week and harvested when tumors reached 1000 mm 3 . For study of normal development, blood and tissue were harvested at 4, 6 and 9 weeks of age in TTR-IGF-I and wt mice. TTR-IGF-I and TTR-IGF-I/ErbB2 bigenic mice showed a moderate 35% increase in circulating total IGF-I compared to ErbB2 and wt control mice. Elevation of circulating IGF-I had no effect upon pubertal mammary gland development. The transgenic increase in IGF-I alone wasn't sufficient to initiate mammary tumorigenesis. Elevated circulating IGF-I had no effect upon ErbB2-induced mammary tumorigenesis or metastasis, with median time to tumor formation being 30 wks and 33 wks in TTR-IGF-I/ErbB2 bigenic and ErbB2 mice respectively (p = 0.65). Levels of IGF-I in lysates from ErbB2/TTR-IGF-I tumors compared to ErbB2 was elevated in a similar manner to the circulating IGF-I, however, there was no effect on the rate of tumor growth (p = 0.23). There were no morphological differences in tumor type (solid adenocarcinomas) between bigenic and ErbB2 mammary glands. Using the first transgenic animal model to

  18. Activation of Akt1 accelerates carcinogen-induced tumorigenesis in mammary gland of virgin and post-lactating transgenic mice

    International Nuclear Information System (INIS)

    Wu, Yanyuan; Kim, Juri; Elshimali, Yayha; Sarkissyan, Marianna; Vadgama, Jaydutt V

    2014-01-01

    Data from in vivo and in vitro studies suggest that activation of Akt regulates cell survival signaling and plays a key role in tumorigenesis. Hence, transgenic mice were created to explore the oncogenic role of Akt1 in the development of mammary tumors. The transgenic mice were generated by expressing myristoylated-Akt1 (myr-Akt1) under the control of the MMTV-LTR promoter. The carcinogen 7, 12 dimethyl-1,2-benzanthracene (DMBA) was used to induce tumor formation. The MMTV driven myr-Akt1 transgene expression was detected primarily in the mammary glands, uterus, and ovaries. The expression level increased significantly in lactating mice, suggesting that the response was hormone dependent. The total Akt expression level in the mammary gland was also higher in the lactating mice. Interestingly, the expression of MMTVmyr-Akt1 in the ovaries of the transgenic mice caused significant increase in circulating estrogen levels, even at the post-lactation stage. Expression of myr-Akt1 in mammary glands alone did not increase the frequency of tumor formation. However, there was an increased susceptibility of forming mammary tumors induced by DMBA in the transgenic mice, especially in mice post-lactation. Within 34 weeks, DMBA induced mammary tumors in 42.9% of transgenic mice post-lactation, but not in wild-type mice post-lactation. The myr-Akt1 mammary tumors induced by DMBA had increased phosphorylated-Akt1 and showed strong expression of estrogen receptor (ERα) and epidermal growth factor receptor (EGFR). In addition, Cyclin D1 was more frequently up-regulated in mammary tumors from transgenic mice compared to tumors from wild-type mice. Overexpression of Cyclin D1, however, was not completely dependent on activated Akt1. Interestingly, mammary tumors that had metastasized to secondary sites had increased expression of Twist and Slug, but low expression of Cyclin D1. In summary, the MMTVmyr-Akt1 transgenic mouse model could be useful to study mechanisms of ER

  19. The Role of PTHrP in Mammary Gland Development and Tumorigenesis

    National Research Council Canada - National Science Library

    Wysolmerski, John

    1999-01-01

    .... The PTHrP receptor is expressed throughout the sub-epidermal mesenchyme. In those mesenchymal cells closest to the mammary epithelial bud, PTHrP induces a change in cell fate allowing those cells to become functional mammary mesenchymal cells...

  20. Over-expression of ST3Gal-I promotes mammary tumorigenesis

    DEFF Research Database (Denmark)

    Picco, Gianfranco; Julien, Sylvain; Brockhausen, Inka

    2010-01-01

    and lactating mammary glands, the stomach, lungs and intestine. Although no obvious defects were observed in the fully developed mammary gland, when these mice were crossed with PyMT mice, a highly significant decrease in tumor latency was observed compared to the PyMT mice on an identical background...

  1. NMR characteristics of rat mammary tumors

    International Nuclear Information System (INIS)

    Osbakken, M.; Kreider, J.; Taczanowsky, P.

    1984-01-01

    12 rats were injected intradermally with 13762A rat mammary adenocarcinoma (1 x 10/sup 6/ cells). 3 rats died before completion of the study and 2 rat had tumor regression; the first 3 were excluded from data analysis. NMR imaging with a 1.5K gauss resistive magnet at 2, 3, 4, and 5 weeks after injection demonstrated increasing tumor mass. Saturation recovery (SR), inversion recovery (IR), and spin echo (SE) pulse sequence images and T/sub 1/ calculation were done for tumor characterization. (Tumor size was too small to identify at 2 weeks.) 3 rats were sacrificed after the last 3 imaging periods for histological studies, done to distinguish solid tumor mass from necrosis. Planimetry of tumor areas showed that as tumors grew in size, the ratio of necrotic area to area of solid tumor increased (week 3 = .3 +- .11; week 4 = .45 +- .07; week 5 = .51 +- 05); simultaneous calculated T/sub 1/ values also increased (week 3 = .35 +- .15; week 4 = .45 +- .06; week 5 = .42 +- 03). Qualitative NMR image T/sub 1/ values also increased as evidenced by progression of SR and IR tumor image intensity from very bright compared to the rest of the body at week 3 to less intense than other structures at week 5. These findings indicate that change in T/sub 1/ may be secondary to the pathophysiological change in the tumor (the increasing in necrosis, associated with increased free water). Thus, the range of T/sub 1/ values obtained in tumors in this study (and in previous studies) may be due to change in tumor physiology and anatomy. Careful correlation of histological with NMR data may allow ultimate use of NMR relaxation characteristics for determination of the physiological state of tumors

  2. Potential Therapeutic Uses of p19ARF Mimics in Mammary Tumorigenesis

    National Research Council Canada - National Science Library

    Hann, Stephen R

    2005-01-01

    Since many breast tumors have deregulated c-Myc we hypothesize that an ARF mimic would be a valuable therapeutic agent for breast cancer to inhibit c-Myc-induced transformation/tumorigenesis without...

  3. Pomegranate exerts chemoprevention of experimentally induced mammary tumorigenesis by suppression of cell proliferation and induction of apoptosis.

    Science.gov (United States)

    Bishayee, Anupam; Mandal, Animesh; Bhattacharyya, Piyali; Bhatia, Deepak

    2016-01-01

    Breast cancer is the second leading cause of cancer-related death in women in the United States and discovery and development of safe chemopreventive drugs is urgently needed. The fruit pomegranate (Punica granatum) is gaining importance because of its various health benefits. This study was initiated to investigate chemopreventive potential of a pomegranate emulsion (PE) against 7,12-dimethylbenz(a)anthracene (DMBA) rat mammary carcinogenesis. The animals were orally administered with PE (0.2-5.0 g/kg), starting 2 wk before and 16 wk following DMBA treatment. PE exhibited a striking reduction of DMBA-induced mammary tumor incidence, total tumor burden, and reversed histopathological changes. PE dose-dependently suppressed cell proliferation and induced apoptosis in mammary tumors. Immunohistochemical studies showed that PE increased intratumor Bax, decreased Bcl2 and manifested a proapoptotic shift in Bax/Bcl2 ratio. In addition, our gene expression study showed PE-mediated upregulation of Bad, caspase-3, caspase-7, caspase-9, poly (ADP ribose) polymerase and cytochrome c in mammary tumors. Thus, PE exerts chemoprevention of mammary carcinogenesis by suppressing cell proliferation and inducing apoptosis mediated through upregulation of Bax and downregulation of Bcl2 in concert with caspase cascades. Pomegranate bioactive phytoconstituents could be developed as a chemopreventive drug to reduce the risk of breast cancer.

  4. Loss of Panx1 Impairs Mammary Gland Development at Lactation: Implications for Breast Tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Michael K G Stewart

    Full Text Available Pannexin1 (Panx1 subunits oligomerize to form large-pore channels between the intracellular and extracellular milieu that have been shown to regulate proliferation, differentiation and cell death mechanisms. These key cellular responses are ultimately necessary for normal tissue development and function but the role of Panx1 in development, differentiation and function in many tissues remains unexplored, including that of the breast. Panx1 was identified to be expressed in the mammary gland through western blot and immunofluorescent analysis and is dynamically upregulated during pregnancy and lactation. In order to evaluate the role of Panx1 in the context of mammary gland development and function, Panx1-/- mice were evaluated in comparison to wild-type mice in the mammary glands of virgin, lactating and involuting mice. Our results revealed that Panx1 ablation did not affect virgin or involuting mammary glands following histological and whole mount analysis. Panx1 was necessary for timely alveolar development during early lactation based on a decreased number of alveolar lumen following histological analysis and reduced proliferation following Ki67 immunofluorescent labelling. Importantly, the loss of Panx1 in lactating mammary glands did not overtly affect epithelial or secretory differentiation of the mammary gland suggesting that Panx1 is not critical in normal mammary gland function. In addition, PANX1 mRNA expression was correlated with negative clinical outcomes in patients with breast cancer using in silico arrays. Together, our results suggest that Panx1 is necessary for timely alveolar development following the transition from pregnancy to lactation, which may have implications extending to patients with breast cancer.

  5. Expression analysis of the mouse S100A7/psoriasin gene in skin inflammation and mammary tumorigenesis

    International Nuclear Information System (INIS)

    Webb, Meghan; Myal, Yvonne; Shiu, Robert; Murphy, Leigh C; Watson, Peter H; Emberley, Ethan D; Lizardo, Michael; Alowami, Salem; Qing, Gefei; Alfia'ar, Abdullah; Snell-Curtis, Linda J; Niu, Yulian; Civetta, Alberto

    2005-01-01

    The human psoriasin (S100A7) gene has been implicated in inflammation and tumor progression. Implementation of a mouse model would facilitate further investigation of its function, however little is known of the murine psoriasin gene. In this study we have cloned the cDNA and characterized the expression of the potential murine ortholog of human S100A7/psoriasin in skin inflammation and mammary tumorigenesis. On the basis of chromosomal location, phylogenetic analysis, amino acid sequence similarity, conservation of a putative Jab1-binding motif, and similarities of the patterns of mouse S100A7/psoriasin gene expression (measured by RT-PCR and in-situ hybridization) with those of human S100A7/psoriasin, we propose that mouse S100A7/psoriasin is the murine ortholog of human psoriasin/S100A7. Although mouse S100A7/psoriasin is poorly conserved relative to other S100 family members, its pattern of expression parallels that of the human psoriasin gene. In murine skin S100A7/psoriasin was significantly upregulated in relation to inflammation. In murine mammary gland expression is also upregulated in mammary tumors, where it is localized to areas of squamous differentiation. This mirrors the context of expression in human tumor types where both squamous and glandular differentiation occur, including cervical and lung carcinomas. Additionally, mouse S100A7/psoriasin possesses a putative Jab1 binding motif that mediates many downstream functions of the human S100A7 gene. These observations and results support the hypothesis that the mouse S100A7 gene is structurally and functionally similar to human S100A7 and may offer a relevant model system for studying its normal biological function and putative role in tumor progression

  6. The Role of DN-GSK3b in Mammary Tumorigenesis

    Science.gov (United States)

    2007-07-01

    transcription factors and dramatically increases their transcriptional activity. Genes up- regulated by TCF/LEF include embryologic genes, such as siamois...in transgenic mice that overexpress Axin, the expression of cyclin D1 is attenuated and increased apoptosis occurs in the mammary epithelia (33

  7. Epidermal growth factor in mammary glands and milk from rats

    DEFF Research Database (Denmark)

    Thulesen, J; Raaberg, Lasse; Nexø, Ebba

    1993-01-01

    Epidermal growth factor (EGF) is one of the major growth-promoting agents in milk. Using immunohistochemistry we localized EGF in the mammary glands of lactating rats to the luminal border of the secretory cells. Following proteolytic pretreatment of the histological sections, the EGF-immunoreact......Epidermal growth factor (EGF) is one of the major growth-promoting agents in milk. Using immunohistochemistry we localized EGF in the mammary glands of lactating rats to the luminal border of the secretory cells. Following proteolytic pretreatment of the histological sections, the EGF...

  8. Mammary carcinogenesis in rats: basic facts and recent results in Brookhaven

    International Nuclear Information System (INIS)

    Shellabarger, C.J.; Stone, J.P.; Holtzman, s.

    1982-01-01

    Some research results from experiments investigating neutron-induced mammary carcinogenesis in rats are presented. The additive effects of neutrons and 3-methylcholanthrene on mammary adenocarcinoma were determined. Synergism between diethylstilbestrol and neutrons was likewise studied. Differences in mammary neoplastic response between strains of laboratory rats was also investigated

  9. Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation.

    Science.gov (United States)

    Reddy, Jay P; Peddibhotla, Sirisha; Bu, Wen; Zhao, Jing; Haricharan, Svasti; Du, Yi-Chieh Nancy; Podsypanina, Katrina; Rosen, Jeffrey M; Donehower, Larry A; Li, Yi

    2010-02-23

    p53, apoptosis, and senescence are frequently activated in preneoplastic lesions and are barriers to progression to malignancy. These barriers have been suggested to result from an ATM-mediated DNA damage response (DDR), which may follow oncogene-induced hyperproliferation and ensuing DNA replication stress. To elucidate the currently untested role of DDR in breast cancer initiation, we examined the effect of oncogene expression in several murine models of breast cancer. We did not observe a detectable DDR in early hyperplastic lesions arising in transgenic mice expressing several different oncogenes. However, DDR signaling was strongly induced in preneoplastic lesions arising from individual mammary cells transduced in vivo by retroviruses expressing either PyMT or ErbB2. Thus, activation of an oncogene after normal tissue development causes a DDR. Furthermore, in this somatic ErbB2 tumor model, ATM, and thus DDR, is required for p53 stabilization, apoptosis, and senescence. In palpable tumors in this model, p53 stabilization and apoptosis are lost, but unexpectedly senescence remains in many tumor cells. Thus, this murine model fully recapitulates early DDR signaling; the eventual suppression of its endpoints in tumorigenesis provides compelling evidence that ErbB2-induced aberrant mammary cell proliferation leads to an ATM-mediated DDR that activates apoptosis and senescence, and at least the former must be overcome to progress to malignancy. This in vivo study also uncovers an unexpected effect of ErbB2 activation previously known for its prosurvival roles, and suggests that protection of the ATM-mediated DDR-p53 signaling pathway may be important in breast cancer prevention.

  10. Developmental and lactational exposure to dieldrin alters mammary tumorigenesis in Her2/neu transgenic mice.

    Directory of Open Access Journals (Sweden)

    Heather L Cameron

    Full Text Available Breast cancer is the most common cancer in Western women and while its precise etiology is unknown, environmental factors are thought to play a role. The organochlorine pesticide dieldrin is a persistent environmental toxicant thought to increase the risk of breast cancer and reduce survival in the human population. The objective of this study was to define the effect of developmental exposure to environmentally relevant concentrations of dieldrin, on mammary tumor development in the offspring. Sexually mature FVB-MMTV/neu female mice were treated with vehicle (corn oil, or dieldrin (0.45, 2.25, and 4.5 microg/g body weight daily by gavage for 5 days prior to mating and then once weekly throughout gestation and lactation until weaning. Dieldrin concentrations were selected to produce serum levels representative of human background body burdens, occupational exposure, and overt toxicity. Treatment had no effect on litter size, birth weight or the number of pups surviving to weaning. The highest dose of dieldrin significantly increased the total tumor burden and the volume and number of tumors found in the thoracic mammary glands. Increased mRNA and protein expression of the neurotrophin BDNF and its receptor TrkB was increased in tumors from the offspring of dieldrin treated dams. This study indicates that developmental exposure to the environmental contaminant dieldrin causes increased tumor burden in genetically predisposed mice. Dieldrin exposure also altered the expression of BNDF and TrkB, novel modulators of cancer pathogenesis.

  11. Extracellular matrix control of mammary gland morphogenesis and tumorigenesis: insights from imaging

    Energy Technology Data Exchange (ETDEWEB)

    Ghajar, Cyrus M; Bissell, Mina J

    2008-10-23

    The extracellular matrix (ECM), once thought to solely provide physical support to a tissue, is a key component of a cell's microenvironment responsible for directing cell fate and maintaining tissue specificity. It stands to reason, then, that changes in the ECM itself or in how signals from the ECM are presented to or interpreted by cells can disrupt tissue organization; the latter is a necessary step for malignant progression. In this review, we elaborate on this concept using the mammary gland as an example. We describe how the ECM directs mammary gland formation and function, and discuss how a cell's inability to interpret these signals - whether as a result of genetic insults or physicochemical alterations in the ECM - disorganizes the gland and promotes malignancy. By restoring context and forcing cells to properly interpret these native signals, aberrant behavior can be quelled and organization re-established. Traditional imaging approaches have been a key complement to the standard biochemical, molecular, and cell biology approaches used in these studies. Utilizing imaging modalities with enhanced spatial resolution in live tissues may uncover additional means by which the ECM regulates tissue structure, on different length scales, through its pericellular organization (short-scale) and by biasing morphogenic and morphostatic gradients (long-scale).

  12. Decorin is one of the proteoglycans expressed in Walker 256 rat mammary carcinoma

    Directory of Open Access Journals (Sweden)

    S.M. Oba-Shinjo

    2003-08-01

    Full Text Available Proteoglycan and glycosaminoglycan content was analyzed in a model of rat mammary carcinoma to study the roles of these compounds in tumorigenesis. Hyaluronic acid and proteoglycans bearing chondroitin and/or dermatan sulfate chains were detected in solid tumors obtained after subcutaneous inoculation of Walker 256 rat carcinoma cells. About 10% of sulfated glycosaminoglycan chains corresponded to heparan sulfate. The small leucine-rich proteoglycan, decorin, was identified as one of the proteoglycans, in addition to others of higher molecular weight, by cross-reaction with an antiserum raised against pig laryngeal decorin and by N-terminal amino acid sequencing. Decorin was separated from other proteoglycans by hydrophobic chromatography and its complete structure was determined. It has a molecular weight of about 85 kDa and a dermatan chain of 45 kDa with 4-sulfated disaccharides. After degradation of the glycosaminoglycan chain, three core proteins of different molecular weight (36, 46 and 56 kDa were identified. The presence of hyaluronic acid and decorin has been reported in a variety of tumors and tumor cells. In the Walker 256 mammary carcinoma model, hyaluronic acid may play an important role in tumor progression, since it provides a more hydrated extracellular matrix. On the other hand, decorin, which is expressed by stromal cells, represents a host defense response to tumor growth.

  13. Interrogation of the rat mammary gland using intraductal impedance spectroscopy

    International Nuclear Information System (INIS)

    Young, E F; Quinn, D A; Davies, R J

    2010-01-01

    Extant technologies for the detection of breast cancer exploit changes in the morphology of the mammary ductal epithelial network and can involve ionizing radiation. Intraductal surveillance of mammary epithelium has the potential to allow for earlier detection based on changes in function of the epithelium. This study investigated the feasibility of using intraductal impedance spectroscopy (IIS) to assess changes in resistance in the mammary epithelium in a small group of female rats in resting, pregnant and ultimately lactating states. In resting rats, intraductal surveillance was able to detect only a single resistive capacitance (RC). In pregnant animals, a second RC became evident in the frequency range between 1 and 190 Hz. The real resistance of this low frequency RC increased when measurements were made after the animals had begun lactating. Equivalent circuit modeling revealed this increase to be a 1.7-fold change from pregnancy to lactation. A model of tight junction closure in the context of ductal expansion is proposed. These results suggest that physiologic measurements can be made in rodent mammary epithelium using this technique allowing for assessment of function in normal and disease states

  14. STUDY OF OVARIAN CHANGES IN RATS WITH MAMMARY CARCINOMAS

    Directory of Open Access Journals (Sweden)

    Maja Zečević

    2013-03-01

    Full Text Available The aim of this study was to estimate ovarian changes in 7,12 dimethylbenz (α anthracene (DMBA induced rat mammary carcinomas. The study was carried out on female virgin albino Wistar rats (n=35, age=35-37days, body mass 120-140g, divided into control (n=10 and experimental group (n=25. Anesthetised animals of experimental group were inoculated with 2 mg mixture (1 mg of DMBA and 1 mg of cholesterol-buffer into the fifth left mammary gland. The animals were sacrificed 90 days after implantation, and ovaries and mammary glands were investigated. Mammary gland carcinomas (in situ and/or invasive were pathohistologically verified in 19 experimental animals. Histological, histochemical, and immunohistochemical (cytokeratin AE1/AE3 and PCNA studies of ovaries were performed.Besides non-neoplastic changes, such as decrease in ovary’s volume, reduction in the rate of follicular development and numerous corpora lutea formation were found in the vicinity of preneoplastic changes: papillomatous epithelial hyperplasia and inclusion cysts, microglandular formations with dysplasia and seromucinous microcystic formation. Intensive diffuse PCNA expression was present in the epithelium of glandlike structures, follicular and inclusion cysts.These morphological changes confirmed that DMBA is a pluripotent carcinogen capable to induce a wide spectrum of preneoplastic lesions in the ovaries. The present dilemma is whether the changes described are the consequence of the direct effects of DMBA or of hormonal activity of the induced breast carcinomas, or both.

  15. Maternal consumption of canola oil suppressed mammary gland tumorigenesis in C3(1) TAg mice offspring

    International Nuclear Information System (INIS)

    Ion, Gabriela; Akinsete, Juliana A; Hardman, W Elaine

    2010-01-01

    Maternal consumption of a diet high in omega 6 polyunsaturated fats (n-6 PUFA) has been shown to increase risk whereas a diet high in omega 3 polyunsaturated fats (n-3 PUFA) from fish oil has been shown to decrease risk for mammary gland cancer in female offspring of rats. The aim of this study was to determine whether increasing n-3 PUFA and reducing n-6 PUFA by using canola oil instead of corn oil in the maternal diet might reduce the risk for breast cancer in female offspring. Female SV 129 mice were divided into two groups and placed on diets containing either 10% w/w corn oil (which is 50% n-6 PUFA, control diet) or 10% w/w canola oil (which is 20% n-6 PUFA, 10% n-3 PUFA, test diet). After two weeks on the diets the females were bred with homozygous C3(1) TAg transgenic mice. Mother mice consumed the assigned diet throughout gestation and nursing of the offspring. After weaning, all female offspring were maintained on the control diet. Compared to offspring of mothers fed the corn oil diet (CO/CO group), offspring of mothers fed the canola oil diet (CA/CO group) had significantly fewer mammary glands with tumors throughout the experiment. At 130 days of age, the CA/CO group had significantly fewer tumors per mouse (multiplicity); the tumor incidence (fraction of mice with any tumor) and the total tumor weight (per mouse that developed tumor) was less than one half that of the CO/CO group. At 170 days of age, the total tumor weight per mouse was significantly less in the CA/CO group and if a tumor developed the rate of tumor growth rate was half that of CO/CO group. These results indicate that maternal consumption of canola oil was associated with delayed appearance of mammary gland tumors and slowed growth of the tumors that developed. Substituting canola oil for corn oil is an easy dietary change for people to make; such a change to the maternal diet may decrease risk for breast cancer in the daughter

  16. Age and radiation sensitivity of rat mammary clonogenic cells

    International Nuclear Information System (INIS)

    Shimada, Yoshiya; Yasukawa-Barnes, J.; Kim, R.Y.; Gould, M.N.; Clifton, K.H.

    1994-01-01

    The relative risk of breast cancer is very high among women who were exposed to ionizing radiation during or before puberty. In the current studies, the surviving fractions of clonogenic mammary cells of groups of virgin rats were estimated after single exposures to 137 Cs γ rays at intervals from 1 to 12 weeks after birth. The radiosensitivity of clonogens from prepubertal rats was high and changed with the onset of puberty at between 4 and 6 weeks of age. By this time, the increase in the size of the clonogenic cell subpopulation was slowing and differentiation of terminal mammary end buds and alveolar structures was occurring. Analysis of the relationship of clonogen survival and radiation dose according to the α/β model showed that the exponential αD term predominated at the second and fourth weeks of age. By the eighth week of age, the βD 2 term had come to predominate and the survival curve had a pronounced initial convex shoulder. Further experiments are required to determine whether there is an association between the high sensitivity of the prepubertal and pubertal mammary clonogens to radiation killing and a high susceptibility to radiogenic initiation of cancer. 24 refs., 4 figs., 1 tab

  17. Tamoxifen induces regression of estradiol-induced mammary cancer in ACI.COP-Ept2 rat model

    OpenAIRE

    Ruhlen, Rachel L.; Willbrand, Dana M.; Besch-Williford, Cynthia L.; Ma, Lixin; Shull, James D.; Sauter, Edward R.

    2008-01-01

    The ACI rat is a unique model of human breast cancer in that mammary cancers are induced by estrogen without carcinogens, irradiation, xenografts or transgenic manipulations. We sought to characterize mammary cancers in a congenic variant of the ACI rat, the ACI.COP-Ept2. All rats with estradiol implants developed mammary cancers in 5–7 months. Rats bearing estradiol-induced mammary cancers were treated with tamoxifen for three weeks. Tamoxifen reduced tumor mass, measured by magnetic resonan...

  18. Cadmium in milk and mammary gland in rats and mice

    International Nuclear Information System (INIS)

    Petersson Grawe, K.; Oskarsson, A.

    2000-01-01

    The purpose of the present investigation was to study the uptake of cadmium in mammary tissue, effects on milk secretion and composition, and lactational transport of cadmium to the sucklings. Cadmium exposure during lactation resulted in retention of cadmium in the mammary tissue in mice and rats. The uptake of cadmium in the mammary tissue was rapid, as shown in lactating mice by whole-body autoradiography 4 h after an intravenous injection of a tracer dose of 109 CdCl 2 . Retention of cadmium in kidneys of suckling pups was observed in the autoradiograms at 7 days after exposure of the dams. Lactating rats were intravenously infused with 109 CdCl 2 in 0.9% saline via osmotic minipumps from day 3 to day 16 after parturition. The cadmium dose given was 0, 8.8, 62 and 300 μg Cd/kg body wt. per day. Plasma and milk were collected at day 10 and 16 after parturition. Plasma cadmium levels in dams increased from day 10 to day 16. Cadmium levels were higher in milk than in plasma, with milk/plasma ratios varying from 2 to 6. Zinc levels in milk were positively correlated to cadmium levels in milk (r 2 =0.26; P=0.03). In milk, 109 Cd was distributed in fat (46-52%), casein fraction (40-46%), and whey fraction (6-8%). There was a high correlation between cadmium concentrations in pups' kidney and cadmium concentrations in dam's milk (r 2 =0.98; P 109 Cd was bound to metallothionein in mammary tissue. The fraction of radiolabelled cadmium bound to metallothionein increased in a dose-dependent manner in both the liver (88-98%) and mammary tissue (57-80%). The present results indicate a low transfer of cadmium to the suckling pup, which might be due to binding of cadmium to metallothionein in the mammary tissue. However, during the susceptible developmental period even a low cadmium exposure may be of concern. (orig.)

  19. Characterization of synergistic anti-cancer effects of docosahexaenoic acid and curcumin on DMBA-induced mammary tumorigenesis in mice

    International Nuclear Information System (INIS)

    Siddiqui, Rafat A; Harvey, Kevin A; Walker, Candace; Altenburg, Jeffrey; Xu, Zhidong; Terry, Colin; Camarillo, Ignacio; Jones-Hall, Yava; Mariash, Cary

    2013-01-01

    The major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. One approach to overcoming this problem is to use combinations of nutrients to induce synergistic effects. The objective of this research was to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA), an omega-3 fatty acid present in cold-water fish, and curcumin (CCM), an herbal nutrient present in turmeric, in an in vivo model of DMBA-induced mammary tumorigenesis in mice. We used the carcinogen DMBA to induce breast tumors in SENCAR mice on control, CCM, DHA, or DHA + CCM diets. Appearance and tumor progression were monitored daily. The tumors were harvested 15 days following their first appearance for morphological and immunohistological analysis. Western analysis was performed to determine expression of maspin and survivin in the tumor tissues. Characterization of tumor growth was analyzed using appropriate statistical methods. Otherwise all other results are reported as mean ± SD and analyzed with one-way ANOVA and Tukey’s post hoc procedure. Analysis of gene microarray data indicates that combined treatment with DHA + CCM altered the profile of “PAM50” genes in the SK-BR-3 cell line from an ER - /Her-2 + to that resembling a “normal-like” phenotype. The in vivo studies demonstrated that DHA + CCM treatment reduced the incidence of breast tumors, delayed tumor initiation, and reduced progression of tumor growth. Dietary treatment had no effect on breast size development, but tumors from mice on a control diet (untreated) were less differentiated than tumors from mice fed CCM or DHA + CCM diets. The synergistic effects also led to increased expression of the pro-apoptotic protein, maspin, but reduced expression of the anti-apoptotic protein, survivin. The SK-BR-3 cells and DMBA-induced tumors, both with an ER - and Her-2 + phenotype, were affected by the

  20. The Role of Nuclear Receptor Coactivator A1B1 in Growth Factor-Mediated Mammary Tumorigenesis

    Science.gov (United States)

    2007-03-01

    chemotherapies also develop resistance to the treatment , resulting ultimately in the recurrence of breast cancer growth. Interestingly, the mechanism of...gland development, dwarfism and abnormal reproductive function [8]. I want to determine whether the loss of AIB1 in MMTV-Neu mice alters the mammary...study display dwarfism and the retardation of mammary gland growth [9]. At the 4-month time point, I similarly observed an overall decrease in mammary

  1. Susceptibility to radiation-induced mammary carcinoma in genetically resistant Copenhagen rats

    International Nuclear Information System (INIS)

    Kamiya, Kenji; Nitta, Yumiko; Gould, M.N.

    2000-01-01

    The objective of this experiment was to compare the cellular basis of mammary cancer induction by a chemical carcinogen with induction by ionizing radiation in three strains of rats (inbred that have different genetic susceptibilities: COP rats, F344 rats, and WF rats). Rats were given a single intraperitoneal injection of 50 mg MNU/kg body weight as a mammary-tumor-inducing chemical carcinogen and were irradiated with a 3.0 Gy dose of 60 Co gamma rays at a dose rate of 26.58±1.19 cGy/min. The rats were inspected weekly, and they were killed and necropsied whenever palpable tumors were detected or they became moribund. The histopathological and immunohistochemical characteristics of the mammary tumors were investigated. A transplantation experiment using selected primary mammary tumors that developed in COP rats exposed to gamma rays was also performed to investigate the transplantability of mammary tumors induced by ionizing radiation. The sensitivity of the WF and F344 rats and the resistance of the COP rats to mammary carcinoma induction by the chemical carcinogen MNU was confirmed. In contrast to the chemical carcinogens, no difference in susceptibility to radiation induction of mammary carcinomas was detected among the three strains of rats, and immunohistochemical examination indicated that the radiation-induced carcinomas consisted of more highly differentiated cells than the MNU-induced cancers. The results of the experiment appear to support the hypothesis that differentiated mammary gland tissue is more resistant to chemical carcinogens than to cancer induction by radiation. The authors conclude that radiation-induced cancers in rats may develop via different pathways or from different cell populations than chemically induced cancers. (K.H.)

  2. Susceptibility to radiation-induced mammary carcinoma in genetically resistant Copenhagen rats

    Energy Technology Data Exchange (ETDEWEB)

    Kamiya, Kenji; Nitta, Yumiko [Hiroshima Univ. (Japan). Research Inst. for Radiation Biology and Medicine; Gould, M.N.

    2000-07-01

    The objective of this experiment was to compare the cellular basis of mammary cancer induction by a chemical carcinogen with induction by ionizing radiation in three strains of rats (inbred that have different genetic susceptibilities: COP rats, F344 rats, and WF rats). Rats were given a single intraperitoneal injection of 50 mg MNU/kg body weight as a mammary-tumor-inducing chemical carcinogen and were irradiated with a 3.0 Gy dose of {sup 60} Co gamma rays at a dose rate of 26.58{+-}1.19 cGy/min. The rats were inspected weekly, and they were killed and necropsied whenever palpable tumors were detected or they became moribund. The histopathological and immunohistochemical characteristics of the mammary tumors were investigated. A transplantation experiment using selected primary mammary tumors that developed in COP rats exposed to gamma rays was also performed to investigate the transplantability of mammary tumors induced by ionizing radiation. The sensitivity of the WF and F344 rats and the resistance of the COP rats to mammary carcinoma induction by the chemical carcinogen MNU was confirmed. In contrast to the chemical carcinogens, no difference in susceptibility to radiation induction of mammary carcinomas was detected among the three strains of rats, and immunohistochemical examination indicated that the radiation-induced carcinomas consisted of more highly differentiated cells than the MNU-induced cancers. The results of the experiment appear to support the hypothesis that differentiated mammary gland tissue is more resistant to chemical carcinogens than to cancer induction by radiation. The authors conclude that radiation-induced cancers in rats may develop via different pathways or from different cell populations than chemically induced cancers. (K.H.)

  3. Physical Confirmation and Comparative Genomics of the Rat Mammary carcinoma susceptibility 3 Quantitative Trait Locus

    Directory of Open Access Journals (Sweden)

    Saasha Le

    2017-06-01

    Full Text Available Human breast and rat mammary cancer susceptibility are complex phenotypes where complete sets of risk associated loci remain to be identified for both species. We tested multiple congenic rat strains to physically confirm and positionally map rat Mammary carcinoma susceptibility 3 (Mcs3—a mammary cancer resistance allele previously predicted at Rattus norvegicus chromosome 1 (RNO1. The mammary cancer susceptible Wistar Furth (WF strain was the recipient, and the mammary cancer resistant Copenhagen (Cop strain was the RNO1-segment donor for congenics. Inbred WF females averaged 6.3 carcinogen-induced mammary carcinomas per rat. Two WF.Cop congenic strains averaged 2.8 and 3.4 mammary carcinomas per rat, which confirmed Mcs3 as an independently acting allele. Two other WF.Cop congenic strains averaged 6.6 and 8.1 mammary carcinomas per rat, and, thus, did not contain Mcs3. Rat Mcs3 was delimited to 27.8 Mb of RNO1 from rs8149408 to rs105131702 (RNO1:143700228-171517317 of RGSC 6.0/rn6. Human genetic variants with p values for association to breast cancer risk below 10−7 had not been reported for Mcs3 orthologous loci; however, human variants located in Mcs3-orthologous regions with potential association to risk (10−7 < p < 10−3 were listed in some population-based studies. Further, rat Mcs3 contains sequence orthologous to human 11q13/14—a region frequently amplified in female breast cancer. We conclude that Mcs3 is an independently acting mammary carcinoma resistance allele. Human population-based, genome-targeted association studies interrogating Mcs3 orthologous loci may yield novel breast cancer risk associated variants and genes.

  4. Etoricoxib in the Prevention of Rat Mammary Carcinogenesis

    Directory of Open Access Journals (Sweden)

    P. Orendáš

    2007-01-01

    Full Text Available Several experimental studies suggest that non-steroidal antiinflammatory drugs have chemopreventive effects in mammary carcinogenesis. In this study, tumour suppressive effects of a selective inhibitor of cyclooxygenase-2 (COX-2 etoricoxib in the prevention of N-methyl-Nnitrosourea (NMU-induced mammary carcinogenesis in Sprague-Dawley rats were evaluated. Etoricoxib was administered in the diet, at two concentrations: 1 0.01 mg/g (ETO 0.001% and 2 0.025 mg/g (ETO 0.0025%. Although the chemopreventive effects were not statistically significant, remarkable tumour suppressive effects with the concentration of ETO 0.0025% were recorded. The incidence decreased by 4.31% and tumour frequency per group decreased by 6.67% when compared to the control group. Latency (the period from carcinogen administration to the first tumour appearance increased by 7.28% in dose-dependent manner. The results of our experiments point to dose-dependent tumour suppressive effects of a higher concentration of etoricoxib (ETO 0.0025% when compared to the control group. They suggest that higher etoricoxib concentrations may enhance its tumour suppressive effects.

  5. Cell proliferation and apoptosis in rat mammary glands following combinational exposure to bisphenol A and genistein

    International Nuclear Information System (INIS)

    Wang, Jun; Jenkins, Sarah; Lamartiniere, Coral A

    2014-01-01

    Humans are exposed to an array of both harmful and beneficial hormonally active compounds in the environment and through diet. Two such chemicals are Bisphenol A (BPA), a plasticizer, and genistein, a component of soy. Prepubertal exposure to BPA increased mammary carcinogenesis, while genistein suppressed cancer in a chemically-induced model of rodent mammary cancer. The purpose of this research was to determine the effects of combinational exposure to genistein and BPA on cell proliferation, apoptosis, and associated proteins as markers of cancer in mammary glands of rats exposed prepubertally to these environmental chemicals. Prepubertal rats (postpartum days (PND) 2–20) were exposed through lactation via nursing dams treated orally with sesame oil (SO), BPA, genistein, or a combination of BPA and genistein (BPA + Gen). Cell proliferation, apoptosis and protein expressions were investigated for mechanistic studies in mammary glands of rats exposed to these environmental chemicals. Prepubertal exposure to genistein increased cell proliferation in mammary glands of PND21 rats, while BPA increased cell proliferation in adult (PND50) rats. Prepubertal combinational exposure to BPA + Gen increased cell proliferation and reduced apoptosis in PND21 rats, but reduced cell proliferation and increased apoptosis in PND50 rats. The altered mechanisms behind these cellular responses appear to be centered on differential protein expression of caspases, PARP, Bad, p21, Akts, PTEN, ER-β and SRCs 1–3, in the rat mammary gland. Prepubertal BPA exposure resulted in increased cell proliferation in mammary glands of PND50 rats, a process associated with increased risk of cancer development in a chemically-induced mammary cancer. On the other hand, genistein stimulated cell proliferation at PND21, a process that correlates with mammary gland maturation and chemoprevention. In contrast to single chemical exposure, combinational exposure to BPA + Gen performed most similarly to

  6. Unique expression pattern of the three insulin receptor family members in the rat mammary gland

    DEFF Research Database (Denmark)

    Hvid, Henning; Klopfleisch, Robert; Vienberg, Sara Gry

    2011-01-01

    mammary gland. Using laser micro-dissection, quantitative RT-PCR and immunohistochemistry, we examined the expression of IR (insulin receptor), IGF-1R (IGF-1 receptor), IRR (insulin receptor-related receptor), ERα (estrogen receptor alpha), ERβ (estrogen receptor beta) and PR (progesteron receptor......) in young, virgin, female Sprague-Dawley rats and compared to expression in reference organs. The mammary gland displayed the highest expression of IRR and IGF-1R. In contrast, low expression of IR transcripts was observed in the mammary gland tissue with expression of the IR-A isoform being 5-fold higher...... than the expression of the IR-B. By immunohistochemistry, expression of IR and IGF-1R was detected in all mammary gland epithelial cells. Expression of ERα and PR was comparable between mammary gland and ovary, whereas expression of ERβ was lower in mammary gland than in the ovary. Finally, expression...

  7. 20neon ion- and x-ray-induced mammary carcinogenesis in female rats

    International Nuclear Information System (INIS)

    Shellabarger, C.J.; Baum, J.W.; Holtzman, S.; Stone, J.P.

    1983-01-01

    One of the proposed uses of heavy ion irradiation is to image lesions of the human female breast. The rat model system was chosen to assess the carcinogenic potential of heavy ion irradiation in the belief that data obtained from rat studies would have a qualitatively predictive value for the human female. Accordingly, female rats were exposed to 20 Ne ions at the BEVALAC and studied for the development of mammary neoplasia for 312 +- 2 days at Brookhaven along with rats exposed concurrently to x-irradiation or to no irradiation. As the dose of either type of radiation was increased the percent of rats with mammary adenocarcinomas, and the percent of rats with mammary fibroadenomas, tended to increase. At a prevalence of 20%, the RBE for 20 Neon ions for mammary adenocarcinomas was estimated to be larger than 5 and for mammary fibroadenomas the RBE was estimated to be less than 2. No conclusion was reached concerning whether or not the RBE might vary with dose. We suggest that 20 Ne ions do have a carcinogenic potential for rat mammary tissue and that this carcinogenic potential is likely to be greater than for x-irradiation. (DT)

  8. A study on mammary gland tumors in rats born of parents irradiated before mating

    International Nuclear Information System (INIS)

    Strel'tsova, V.N.; Pavlenko-Mikhajlov, Yu.N.; Oshchepkov, A.B.

    1982-01-01

    The effect of exposure of male or female rats to radiation 5 days before conception on the frequency of development of mammary tumors in their progeny is described. It was shown that mammary tumor incidence and the rate of their development increase in a population of female rats-descendants of one of parents exposed. Irradiation of would-be mothers produced a stronger blastogenic reaction in their progeny than that of fathers

  9. Does Skeletal Muscle Mass Influence Breast Cancer? Evaluating Mammary Tumorigenesis and Progression in Genetically Hyper-Muscular Mice

    Science.gov (United States)

    2007-07-01

    muscle growth inhibitor myostatin and mice expressing a dominant negative form of the myostatin receptor (MLC-dnActRIIB mice). Mammary cancer was...hypermuscular mice and the results are pending. In the interim we used genetic and pharmacological inhibition of the myostatin pathway to potentially...metabolic syndrome induced by the tumor. However, despite increasing normal muscle growth, myostatin inhibition failed to protect mice from cancer

  10. Association of cellular and molecular responses in the rat mammary gland to 17β-estradiol with susceptibility to mammary cancer

    International Nuclear Information System (INIS)

    Ding, Lina; Zhao, Yang; Warren, Christopher L; Sullivan, Ruth; Eliceiri, Kevin W; Shull, James D

    2013-01-01

    We are using ACI and BN rats, which differ markedly in their susceptibility to 17β-estradiol (E2)-induced mammary cancer, to identify genetic variants and environmental factors that determine mammary cancer susceptibility. The objective of this study was to characterize the cellular and molecular responses to E2 in the mammary glands of ACI and BN rats to identify qualitative and quantitative phenotypes that associate with and/or may confer differences in susceptibility to mammary cancer. Female ACI and BN rats were treated with E2 for 1, 3 or 12 weeks. Mammary gland morphology and histology were examined by whole mount and hematoxylin and eosin (H&E) staining. Cell proliferation and epithelial density were evaluated by quantitative immunohistochemistry. Apoptosis was evaluated by quantitative western blotting and flow cytometry. Mammary gland differentiation was examined by immunohistochemistry. Gene expression was evaluated by microarray, qRT-PCR and quantitative western blotting assays. Extracellular matrix (ECM) associated collagen was evaluated by Picrosirius Red staining and Second Harmonic Generation (SHG) microscopy. The luminal epithelium of ACI rats exhibited a rapid and sustained proliferative response to E2. By contrast, the proliferative response exhibited by the mammary epithelium of BN rats was restrained and transitory. Moreover, the epithelium of BN rats appeared to undergo differentiation in response to E2, as evidenced by production of milk proteins as well as luminal ectasia and associated changes in the ECM. Marked differences in expression of genes that encode proteins with well-defined roles in mammary gland development (Pgr, Wnt4, Tnfsf11, Prlr, Stat5a, Areg, Gata3), differentiation and milk production (Lcn2, Spp1), regulation of extracellular environment (Mmp7, Mmp9), and cell-cell or cell-ECM interactions (Cd44, Cd24, Cd52) were observed. We propose that these cellular and molecular phenotypes are heritable and may underlie, at least in

  11. Investigating the Role of Cooperative Interactions Between the neu Proto-oncogene and the Other erbB Family Members in Rat Mammary Carcinogenesis

    National Research Council Canada - National Science Library

    Gould, Michael

    1998-01-01

    .... To date, all three lines show a low incidence of spontaneous mammary tumorigenesis. The vast majority of tumors that have arisen in the oldest line appear after one year of age and are fibroadenomas...

  12. Low-dose effects of bisphenol A on mammary gland development in rats

    DEFF Research Database (Denmark)

    Egebjerg, Karen Mandrup; Boberg, Julie; Isling, Louise Krag

    2016-01-01

    was to perform a study robust enough to contribute to the risk assessment of BPA and to elucidate possible biphasic dose–response relationships. We investigated mammary gland effects in the offspring at 22, 100, and 400 days of age. Male offspring showed increased mammary outgrowth on pup day (PD) 22 at 0.025 mg...... intraductal hyperplasia in female rats could be associated with an increased risk for developing hyperplastic lesions, which are parallels to early signs of breast neoplasia in women. Collectively, current knowledge on effects of BPA on mammary gland at low doses indicates that highly exposed humans may...

  13. Curcumin Implants, not Curcumin Diet Inhibits Estrogen-Induced Mammary Carcinogenesis in ACI Rats

    Science.gov (United States)

    Bansal, Shyam S.; kausar, Hina; Vadhanam, Manicka V.; Ravoori, Srivani; Pan, Jianmin; Rai, Shesh N.; Gupta, Ramesh C.

    2014-01-01

    Curcumin is widely known for its anti-oxidant, anti-inflammatory and anti-proliferative activities in cell culture studies. However, poor oral bioavailability limited its efficacy in animal and clinical studies. Recently, we developed polymeric curcumin implants that circumvents oral bioavailability issues, and tested their potential against 17β-estradiol (E2)-mediated mammary tumorigenesis. Female ACI rats were administered curcumin either via diet (1,000 ppm) or via polymeric curcumin implants (two 2-cm; 200 mg each; 20% drug load) 4 days prior to grafting a subcutaneous E2 silastic implant (1.2 cm, 9 mg E2). Implants were changed after 4½ months to provide higher curcumin dose at the appearance of palpable tumors. The animals were euthanized after 3 weeks, 3 months and after the tumor incidence reached >80% (~6 months) in control animals. The curcumin administered via implants resulted in significant reduction in both the tumor multiplicity (2±1 vs 5±3; p=0.001) and tumor volume (184±198 mm3 vs 280±141 mm3; p=0.0283); the dietary curcumin, however, was ineffective. Dietary curcumin increased hepatic CYP1A and CYP1B1 activities without any effect on CYP3A4 activity whereas curcumin implants increased both CYP1A and CYP3A4 activities but decreased CYP1B1 activity in presence of E2. Since CYP1A and 3A4 metabolize most of the E2 to its non-carcinogenic 2-OH metabolite and CYP1B1 produces potentially carcinogenic 4-OH metabolite, favorable modulation of these CYPs via systemically delivered curcumin could be one of the potential mechanisms. The analysis of plasma and liver by HPLC showed substantially higher curcumin levels via implants versus the dietary route despite substantially higher dose administered. PMID:24501322

  14. Radix bupleuri Extract Inhibits Hyperplasia of Mammary Gland in Rats

    African Journals Online (AJOL)

    Golden Section, Heilongjiang University of Traditional Chinese Medicine, Haerbin 150010, ... lactation, occupation, sex hormone use, diet, and ... organ weight divided by body weight. .... Figure 1: Histologic images of mammary gland tissues.

  15. Inhibition of rat mammary microsomal oxidation of ethanol to acetaldehyde by plant polyphenols.

    Science.gov (United States)

    Maciel, María Eugenia; Castro, José Alberto; Castro, Gerardo Daniel

    2011-07-01

    We previously reported that the microsomal fraction from rat mammary tissue is able to oxidize ethanol to acetaldehyde, a mutagenic-carcinogenic metabolite, depending on the presence of NADPH and oxygen but not inhibited by carbon monoxide or other cytochrome P450 inhibitors. The process was strongly inhibited by diphenyleneiodonium, a known inhibitor of NADPH oxidase, and by nordihydroguaiaretic acid, an inhibitor of lipoxygenases. This led us to suggest that both enzymes could be involved. With the purpose of identifying natural compounds present in food with the ability to decrease the production of acetaldehyde in mammary tissue, in the present studies, several plant polyphenols having inhibitory effects on lipoxygenases and of antioxidant nature were tested as potential inhibitors of the rat mammary tissue microsomal pathway of ethanol oxidation. We included in the present screening study 32 polyphenols having ready availability and that were also tested against the rat mammary tissue cytosolic metabolism of ethanol to acetaldehyde. Several polyphenols were also able to inhibit the microsomal ethanol oxidation at concentrations as low was 10-50 μM. The results of these screening experiments suggest the potential of several plant polyphenols to prevent in vivo production and accumulation of acetaldehyde in mammary tissue.

  16. Tamoxifen induces regression of estradiol-induced mammary cancer in the ACI.COP-Ept2 rat model.

    Science.gov (United States)

    Ruhlen, Rachel L; Willbrand, Dana M; Besch-Williford, Cynthia L; Ma, Lixin; Shull, James D; Sauter, Edward R

    2009-10-01

    The ACI rat is a unique model of human breast cancer in that mammary cancers are induced by estrogen without carcinogens, irradiation, xenografts or transgenic manipulations. We sought to characterize mammary cancers in a congenic variant of the ACI rat, the ACI.COP-Ept2. All rats with estradiol implants developed mammary cancers in 5-7 months. Rats bearing estradiol-induced mammary cancers were treated with tamoxifen for three weeks. Tamoxifen reduced tumor mass, measured by magnetic resonance imaging, by 89%. Tumors expressed estrogen receptors (ER), progesterone receptor (PR), and Erbb2. ERalpha and PR were overexpressed in tumor compared to adjacent non-tumor mammary gland. Thus, this model is highly relevant to hormone responsive human breast cancers.

  17. Mixtures of environmentally relevant endocrine disrupting chemicals affect mammary gland development in female and male rats

    DEFF Research Database (Denmark)

    Mandrup, Karen Riiber; Johansson, Hanna Katarina Lilith; Boberg, Julie

    2015-01-01

    Estrogenic chemicals are able to alter mammary gland development in female rodents, but little is known on the effects of anti-androgens and mixtures of endocrine disrupting chemicals (EDCs) with dissimilar modes of action. Pregnant rat dams were exposed during gestation and lactation to mixtures...

  18. Inhibition of Mammary Cancer Progression in Fetal Alcohol Exposed Rats by β-Endorphin Neurons.

    Science.gov (United States)

    Zhang, Changqing; Franklin, Tina; Sarkar, Dipak K

    2016-01-01

    Fetal alcohol exposure (FAE) increases the susceptibility to carcinogen-induced mammary cancer progression in rodent models. FAE also decreases β-endorphin (β-EP) level and causes hyperstress response, which leads to inhibition of immune function against cancer. Previous studies have shown that injection of nanosphere-attached dibutyryl cyclic adenosine monophosphate (dbcAMP) into the third ventricle increases the number of β-EP neurons in the hypothalamus. In this study, we assessed the therapeutic potential of stress regulation using methods to increase hypothalamic levels of β-EP, a neuropeptide that inhibits stress axis activity, in treatment of carcinogen-induced mammary cancer in fetal alcohol exposed rats. Fetal alcohol exposed and control Sprague Dawley rats were given a dose of N-Nitroso-N-methylurea (MNU) at postnatal day 50 to induce mammary cancer growth. Upon detection of mammary tumors, the animals were either transplanted with β-EP neurons or injected with dbcAMP-delivering nanospheres into the hypothalamus to increase β-EP peptide production. Spleen cytokines were detected using reverse transcription polymerase chain reaction assays. Metastasis study was done by injecting mammary cancer cells MADB106 into jugular vein of β-EP-activated or control fetal alcohol exposed animals. Both transplantation of β-EP neurons and injection of dbcAMP-delivering nanospheres inhibited MNU-induced mammary cancer growth in control rats, and reversed the effect of FAE on the susceptibility to mammary cancer. Similar to the previously reported immune-enhancing and stress-suppressive effects of β-EP transplantation, injection of dbcAMP-delivering nanospheres increased the levels of interferon-γ and granzyme B and decreased the levels of epinephrine and norepinephrine in fetal alcohol exposed rats. Mammary cancer cell metastasis study also showed that FAE increased incidence of lung tumor retention, while β-EP transplantation inhibited lung tumor growth in

  19. Soy isoflavone exposure through all life stages accelerates 17β-estradiol-induced mammary tumor onset and growth, yet reduces tumor burden, in ACI rats.

    Science.gov (United States)

    Möller, Frank Josef; Pemp, Daniela; Soukup, Sebastian T; Wende, Kathleen; Zhang, Xiajie; Zierau, Oliver; Muders, Michael H; Bosland, Maarten C; Kulling, Sabine E; Lehmann, Leane; Vollmer, Günter

    2016-08-01

    There is an ongoing debate whether the intake of soy-derived isoflavones (sISO) mediates beneficial or adverse effects with regard to breast cancer risk. Therefore, we investigated whether nutritional exposure to a sISO-enriched diet from conception until adulthood impacts on 17β-estradiol (E2)-induced carcinogenesis in the rat mammary gland (MG). August-Copenhagen-Irish (ACI) rats were exposed to dietary sISO from conception until postnatal day 285. Silastic tubes containing E2 were used to induce MG tumorigenesis. Body weight, food intake, and tumor growth were recorded weekly. At necropsy, the number, position, size, and weight of each tumor were determined. Plasma samples underwent sISO analysis, and the morphology of MG was analyzed. Tumor incidence and multiplicity were reduced by 20 and 56 %, respectively, in the sISO-exposed rats compared to the control rats. Time-to-tumor onset was shortened from 25 to 20 weeks, and larger tumors developed in the sISO-exposed rats. The histological phenotype of the MG tumors was independent of the sISO diet received, and it included both comedo and cribriform phenotypes. Morphological analyses of the whole-mounted MGs also showed no diet-dependent differences. Lifelong exposure to sISO reduced the overall incidence of MG carcinomas in ACI rats, although the time-to-tumor was significantly shortened.

  20. Surgery and electrochemotherapy treatment of incompletely excised mammary carcinoma in two male pet rats (Rattus norvegicus)

    OpenAIRE

    LANZA, Andrea; PETTORALI, Michela; BALDI, Alfonso; SPUGNINI, Enrico P.

    2017-01-01

    Two male rats (Rattus norvegicus; 18 and 24 months old), were referred for treatment of large masses located in the axillary area. Following total body radiography and hematological and serum biochemical analysis, the rats were anesthetized, and the masses were surgically removed. Both lesions were diagnosed as mammary carcinoma based on histopathological diagnosis. The tumor beds were treated with two sessions of electrochemotherapy (ECT), two weeks apart. ECT involved cisplatin administrati...

  1. Evaluation of carcinogenic potential of diuron in a rat mammary two-stage carcinogenesis model.

    Science.gov (United States)

    Grassi, Tony Fernando; Rodrigues, Maria Aparecida Marchesan; de Camargo, João Lauro Viana; Barbisan, Luís Fernando

    2011-04-01

    This study aimed to evaluate the carcinogenic potential of the herbicide Diuron in a two-stage rat medium-term mammary carcinogenesis model initiated by 7,12-dimethylbenz(a)anthracene (DMBA). Female seven-week-old Sprague-Dawley (SD) rats were allocated to six groups: groups G1 to G4 received intragastrically (i.g.) a single 50 mg/kg dose of DMBA; groups G5 and G6 received single administration of canola oil (vehicle of DMBA). Groups G1 and G5 received a basal diet, and groups G2, G3, G4, and G6 were fed the basal diet with the addition of Diuron at 250, 1250, 2500, and 2500 ppm, respectively. After twenty-five weeks, the animals were euthanized and mammary tumors were histologically confirmed and quantified. Tumor samples were also processed for immunohistochemical evaluation of the expressions of proliferating cell nuclear antigen (PCNA), cleaved caspase-3, estrogen receptor-α (ER-α), p63, bcl-2, and bak. Diuron treatment did not increase the incidence or multiplicity of mammary tumors (groups G2 to G4 versus Group G1). Also, exposure to Diuron did not alter tumor growth (cell proliferation and apoptosis indexes) or immunoreactivity to ER-α, p63 (myoephitelial marker), or bcl-2 and bak (apoptosis regulatory proteins). These findings indicate that Diuron does not have a promoting potential on mammary carcinogenesis in female SD rats initiated with DMBA.

  2. Soy Components Genistein and Lunasin Regulate E-Cadherin and Wnt Signaling in Mammary Epithelial Cells

    Science.gov (United States)

    Enhanced Wnt/beta-catenin signaling and loss of E-cadherin expression are considered hallmarks of tumorigenesis. We previously showed by microarray gene profiling that dietary intake of soy-based AIN-93G diets altered components of Wnt/beta-catenin signaling in rat mammary epithelial cells. To furth...

  3. Histological analysis of low dose NMU effects in the rat mammary gland

    Directory of Open Access Journals (Sweden)

    Sonnenschein Carlos

    2009-08-01

    Full Text Available Abstract Background Our objective was to assess the histological changes in mammary glands of the female Wistar-Furth rat as a result of low dose exposure to N-nitrosomethylurea (NMU. Methods Groups of 30–40 virgin female rats of between 49–58 days old received a single injection of 10, 20, 30 or 50 mg NMU/kg body weight (BW. A group of 10 control rats received 0.9% NaCl solution only. The formation of palpable mammary gland tumors was assessed weekly and, upon sacrifice at 12, 22 and 25–30 weeks after treatment, we performed a comprehensive histological analysis of all mammary gland lesions and tumors. Results Alongside the predicted increase in tumor number and decrease in tumor latency with increasing NMU dose, we observed a number of microscopic lesions and other epithelial abnormalities in the mammary glands for all NMU doses. Two types of non-neoplastic histological changes were observed in rats exposed to 10 or 20 mg NMU/kg BW: namely, (i an increase in the number of acinar structures often accompanied by secretion into the lumen which is normally associated with pregnancy and lactation, and (ii an increase in the number of epithelial cells sloughed into the lumen of the epithelial ducts. Conclusion This study establishes a baseline for low-dose exposure and defines the histological features in the mammary gland resulting from NMU exposure. Furthermore, this system provides an ideal platform for evaluating the relative susceptibility of animals protected from, or predisposed to, developing cancer through environmental influences.

  4. The Role and Regulation of TNF-Alpha in Normal Rat Mammary Gland During Development and in Breast Cancer

    National Research Council Canada - National Science Library

    Varela, Linda

    1998-01-01

    The pleiotropic cytokine tumor necrosis factor-alpha (TNF) has previously been shown to regulate both the proliferation and differentiation of normal rat mammary epithelial cells (MEC) in primary culture...

  5. Anticancer Potential of Nutraceutical Formulations in MNU-induced Mammary Cancer in Sprague Dawley Rats

    OpenAIRE

    Pitchaiah, Gummalla; Akula, Annapurna; Chandi, Vishala

    2017-01-01

    Background: Nutraceuticals help in combating some of the major health problems of the century including cancer, and ?nutraceutical formulations? have led to the new era of medicine and health. Objective: To develop different nutraceutical formulations and to assess the anticancer potential of nutraceutical formulations in N-methyl-N-nitrosourea (MNU)-induced mammary cancer in Sprague Dawley rats. Materials and Methods: Different nutraceutical formulations were prepared using fine powders of a...

  6. Effect of dietary protein quality and feeding level on milk secretion and mammary protein synthesis in the rat

    International Nuclear Information System (INIS)

    Sampson, D.A.; Jansen, G.R.

    1985-01-01

    Protein synthesis was studied in mammary tissue of rats fed diets deficient in protein quality and/or restricted in food intake throughout gestation and lactation. Diets containing 25% wheat gluten (WG), wheat gluten plus lysine and threonine (WGLT), or casein (C) were pair-fed from conception until day 15 of lactation at 100% or 85% of WG ad libitum consumption (PF100 and PF85, respectively). A seventh group was fed C ad libitum. Rates of protein synthesis were measured in vivo at day 15 of lactation from incorporation of [3- 3 H]phenylalanine. At both PF100 and PF85, fractional and absolute rates of mammary gland protein synthesis were two- to three-fold higher in rats fed C than in those fed WG. Pup weights showed similar treatment effects. Both mammary protein synthesis rates and pup weights were significantly higher in rats fed C at PF85 than rats fed WG ad libitum. Food restriction from PF100 to PF85 depressed pup weights and mammary protein synthesis rates in rats fed WGLT, but had no effect in rats fed WG. These results demonstrate that when food intake is restricted, improvement of protein quality of the maternal diet increases milk output in the rat in association with increased rates of mammary protein synthesis

  7. Late effects of in utero exposure to carcinogens in rats, with special reference to postnatal growth and tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Naito, Y; Takizawa, S; Watanabe, H; Hirose, F [Hiroshima Univ. (Japan). Research Inst. for Nuclear Medicine and Biology

    1976-11-01

    Fifteen-day pregnant Wistar/Furth rats were irradiated with 100 rads of x ray of fast neutron (14.1 MeV). Fast neutron was found to be more effective than x rays in reducing the number of live-births and in retarding the postnatal growth of the offspring. Among the various organs examined, the brain, uterus, spleen and gonads were highly radiosensitive in terms of organ weight. Microscopic examination revealed a marked dysplasia of the ovary in the fast neutron-irradiated rats. Pre-conception irradiation did not cause any deleterious effects on the offspring. No substantial difference was noted in the peripheral blood pictures or on the tumor incidence in rats born from the irradiated female rats. On the other hand, it was noteworthy that N-butylnitrosourea given transplacentally induced 3 cases of brain tumor. The incidence of leukemia and mammary tumor was significantly higher in the irradiated or carcinogen-treated pregnant rats.

  8. Induction of mammary tumors in rat by intraperitoneal injection of NMU: histopathology and estral cycle influence.

    Science.gov (United States)

    Rivera, E S; Andrade, N; Martin, G; Melito, G; Cricco, G; Mohamad, N; Davio, C; Caro, R; Bergoc, R M

    1994-11-11

    In order to obtain an experimental model we induced mammary tumors in female Sprague-Dawley rats. The carcinogen N-nitroso-N-methylurea (NMU) was injected intraperitoneally (i.p.) at doses of 50 mg/kg body weight when animals were 50, 80 and 110 days old. Tumor sizes were measured with a caliper and their growth parameters and histopathological properties were tested. For 100 rats, 88.4% of developed lesions were ductal carcinomas, histologically classified as 52.8% cribiform variety, 30.6% solid carcinoma. Metastases in liver, spleen and lung were present. Other primary tumors were detected with low incidence. The influence of the rat estrous cycle during the first exposure to intraperitoneal NMU injection was studied. The latency period in estrus, proestrus and diestrus was 82 +/- 15, 77 +/- 18 and 79 +/- 18 days, respectively. Tumor incidence was significantly higher in estrus (95.2%) than proestrus (71.4%) or diestrus (77.4), (P rats.

  9. The rat as animal model in breast cancer research: a histopathological study of radiation- and hormone-induced rat mammary tumors

    International Nuclear Information System (INIS)

    Zwieten, M.J. van.

    1984-01-01

    One of the goals of this monograph is to present data on the frequency of mammary neoplasms following irradiation and/or hormone administration in intact and castrated female rats of three strains allowed to live their natural life spans. These data are intended to give an overview of the effects of radiation and hormonal manipulation on the mammary gland based on histological examination of necropsied rats and using standard morphological criteria for mammary tumors. The second goal of this monograph is to provide detailed histological descriptions of the mammary tumors found in the various experimental groups as well as in several groups of untreated control rats. The aims are to examine whether possible strain-related and treatment-related differences in morphology or growth patterns exist, as well as to define the pathogensis of radiation-induced rat mammary tumors through the study of early lesions. An attempt will be made to describe tumor characteristics which may be of comparative value in identifying tumor types (and their induction methods) useful as models for specific human breast neoplasms. A rat mammary tumor classification system reflecting the morphological features useful for comparative purposes is also presented. (Auth.)

  10. Selective effects of whey protein concentrate on glutathione levels and apoptosis in rats with mammary tumors.

    Science.gov (United States)

    Cheng, Shih-Hsuan; Tseng, Yang-Ming; Wu, Szu-Hsien; Tsai, Shih-Meng; Tsai, Li-Yu

    2017-09-01

    Glutathione (GSH) plays an important role in antioxidant defense and regulation of apoptosis. GSH deficiency is related to many diseases, including cancer, and increased GSH levels in cancer cells are associated with chemotherapy resistance because of resistance to apoptosis. In this study, we investigated the effects of whey protein concentrate (WPC), a precursor of GSH, in rats with mammary tumors induced by treatment with 7,12-dimethylbenz(a)anthracene (DMBA). DMBA treatment results in cellular changes that mimic the initiation and promotion of carcinogenesis of breast tissue. We aimed to examine the possible preventive effects of diets containing whey protein on DMBA-induced mammary tumors in rats. The results indicate that WPC (0.334 g/kg) supplementation significantly increased the liver GSH levels by 92%, and were accompanied by low Bax/Bcl-2 ratio (from 5 to 3) and cleaved caspase-3/procaspase-3 ratio (from 2.4 to 1.2) in DMBA-treated rats. Furthermore, tumor GSH levels were decreased by 47% in WPC-supplemented rats, which resulted in increased Bax/Bcl-2 ratio (from 0.9 to 2) and cleaved caspase-3/procaspase-3 ratio (from 1.1 to 2.7). In conclusion, supplementation with WPC could selectively deplete tumor GSH levels and, therefore, WPC supplementation might be a promising strategy to overcome treatment resistance in cancer therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Effects of Dietary Xanthophylls, Canthaxanthin and Astaxanthin on N-Methyl-N-nitrosourea-induced Rat Mammary Carcinogenesis.

    Science.gov (United States)

    Yuri, Takashi; Yoshizawa, Katsuhiko; Emoto, Yuko; Kinoshita, Yuichi; Yuki, Michiko; Tsubura, Airo

    Natural xanthophylls, canthaxanthin and astaxanthin are known to exhibit anticancer activity. However, the dietary effects of canthaxanthin and astaxanthin on N-methyl-N-nitrosourea (MNU)-induced mammary cancer remain controversial, and their mechanisms of action have not been clearly identified. Three-week-old female Sprague-Dawley rats were fed a xanthophyll-free (basal diet) diet or experimental diets containing canthaxanthin or astaxanthin (0.04% and 0.4%) for 5 weeks (until 8 weeks of age), after which all rats were provided the basal diet (n=15 each). Rats were administered MNU at 6 weeks of age, and the incidence of mammary tumors at 20 weeks of age was compared. The expression of adiponectin in mammary adipose tissues taken at 7 weeks of age was also compared. Compared to the basal diet group, the 0.4% (but not the 0.04%) astaxanthin diet significantly reduced the incidence of palpable mammary carcinoma (92% vs. 42%; p<0.05), while the low and high canthaxanthin diets produced no significant inhibition. Adiponectin immunoblotting showed significantly higher expression in the 0.4% astaxanthin diet group, while the other groups were similar to the basal diet group. High concentrations of astaxanthin suppress MNU-induced mammary carcinoma. Changes in adiponectin may be involved in the mechanism of action. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  12. Diagnostic PET Imaging of Mammary Microcalcifications Using 64Cu-DOTA-Alendronate in a Rat Model of Breast Cancer.

    Science.gov (United States)

    Ahrens, Bradley J; Li, Lin; Ciminera, Alexandra K; Chea, Junie; Poku, Erasmus; Bading, James R; Weist, Michael R; Miller, Marcia M; Colcher, David M; Shively, John E

    2017-09-01

    The development of improved breast cancer screening methods is hindered by a lack of cancer-specific imaging agents and effective small-animal models to test them. The purpose of this study was to evaluate 64 Cu-DOTA-alendronate as a mammary microcalcification-targeting PET imaging agent, using an ideal rat model. Our long-term goal is to develop 64 Cu-DOTA-alendronate for the detection and noninvasive differentiation of malignant versus benign breast tumors with PET. Methods: DOTA-alendronate was synthesized, radiolabeled with 64 Cu, and administered to normal or tumor-bearing aged, female, retired breeder Sprague-Dawley rats for PET imaging. Mammary tissues were subsequently labeled and imaged with light, confocal, and electron microscopy to verify microcalcification targeting specificity of DOTA-alendronate and elucidate the histologic and ultrastructural characteristics of the microcalcifications in different mammary tumor types. Tumor uptake, biodistribution, and dosimetry studies were performed to evaluate the efficacy and safety of 64 Cu-DOTA-alendronate. Results: 64 Cu-DOTA-alendronate was radiolabeled with a 98% yield. PET imaging using aged, female, retired breeder rats showed specific binding of 64 Cu-DOTA-alendronate in mammary glands and mammary tumors. The highest uptake of 64 Cu-DOTA-alendronate was in malignant tumors and the lowest uptake in benign tumors and normal mammary tissue. Confocal analysis with carboxyfluorescein-alendronate confirmed the microcalcification binding specificity of alendronate derivatives. Biodistribution studies revealed tissue alendronate concentrations peaking within the first hour, then decreasing over the next 48 h. Our dosimetric analysis demonstrated a 64 Cu effective dose within the acceptable range for clinical PET imaging agents and the potential for translation into human patients. Conclusion: 64 Cu-DOTA-alendronate is a promising PET imaging agent for the sensitive and specific detection of mammary tumors as

  13. Anticancer Potential of Nutraceutical Formulations in MNU-induced Mammary Cancer in Sprague Dawley Rats.

    Science.gov (United States)

    Pitchaiah, Gummalla; Akula, Annapurna; Chandi, Vishala

    2017-01-01

    Nutraceuticals help in combating some of the major health problems of the century including cancer, and 'nutraceutical formulations' have led to the new era of medicine and health. To develop different nutraceutical formulations and to assess the anticancer potential of nutraceutical formulations in N-methyl-N-nitrosourea (MNU)-induced mammary cancer in Sprague Dawley rats. Different nutraceutical formulations were prepared using fine powders of amla, apple, garlic, onion, papaya, turmeric, and wheat grass with and without cow urine distillate. Total phenolic content, acute oral toxicity, and microbial load of nutraceutical formulations were assessed. The anticancer potential of nutraceutical formulations was evaluated against MNU-induced mammary cancer in female Sprague Dawley rats. Improvement in total phenolic content was significant ( P safe to use in animals. Microbial load was within the limits. Significant longer tumor-free days ( P apple, garlic, onion, papaya, turmeric, and wheat grass with and without cow urine distillate. Total phenolic content, acute oral toxicity, and microbial load of nutraceutical formulations were assessed. The anticancer potential of nutraceutical formulations was evaluated against MNU-induced mammary cancer in female Sprague Dawley rats. Improvement in total phenolic content was observed after self-fortification process. Toxicity studies showed that the nutraceutical formulations were safe to use in animals. Microbial load was within the limits. Longer tumor-free days, lower tumor incidence, lower tumor multiplicity and tumor burden were observed for nutraceutical formulation-treated groups. This suggests that combination of whole food-based nutraceuticals acted synergistically in the prevention of mammary cancer. Further, the process of fortification enhanced the anticancer potential of nutraceutical formulations. Abbreviations used: HMNU: N-methyl-N-nitrosourea, CAM: Complementary and Alternative Medicine, NF: Nutraceutical

  14. Steroid metabolism and steroid receptors in dimethylbenz(a)anthracene-induced rat mammary tumors

    International Nuclear Information System (INIS)

    Eechaute, W.; de Thibault de Boesinghe, L.; Lacroix, E.

    1983-01-01

    Mammary tumors were induced in rats by treatment with dimethylbenz(a)anthracene. Cytosol receptors for 17 beta-estradiol and progesterone were estimated by means of sucrose density gradient centrifugation, and the metabolism of [ 14 C]progesterone, [ 14 C]testosterone, and 17 beta-[ 14 C]estradiol by minced tumor tissue was studied. The estradiol receptor (ER) and progesterone receptor (PR) levels of the tumors varied considerably from less than 5 to 48 fmol/mg protein for ER and to 243 fmol/mg protein for PR. Considering a receptor level lower than 5 fmol/mg protein to be negative, four groups of tumors were found: ER-negative and PR-negative; ER-positive and PR-negative; ER-negative and PR-positive; ER-positive and PR-positive. In dimethylbenz(a)anthracene-induced tumor tissue, high 5 alpha-reductase and 20 alpha-hydroxysteroid dehydrogenase activities and somewhat lower 3 alpha-hydroxysteroid dehydrogenase and 6 alpha-hydroxylase activities were found. No aromatization was detectable. Steroids, especially estradiol, were also metabolized in a high degree to unextractable metabolites. It was concluded that steroid metabolism of dimethylbenz(a)anthracene-induced rat mammary tumors was not related to the ER and/or PR concentration of tumor tissue

  15. Calcitonin gene-related peptide (CGRP) in the nipple of the rat mammary gland

    DEFF Research Database (Denmark)

    Thulesen, J; Rasmussen, T N; Schmidt, P

    1994-01-01

    The distribution of nerve fibres immunoreactive to calcitonin gene-related peptide (CGRP) was investigated by immunohistochemistry in nipples and mammary glands from lactating and non-lactating rats and compared to the immunoreactivity of other neuropeptides including substance P (SP), neuropepti...... in the nipples of the pregnant (day 10) rats exceeded almost ninefold the maximum concentration of SP (7.7 +/- 2.0 pmol/g).(ABSTRACT TRUNCATED AT 250 WORDS)....... The location of SP-IR appeared to be comparable to CGRP-IR, but in fewer fibres. Dense NPY-IR networks of nerve fibres were closely associated with the fascicles of smooth musculature in the core of the nipple base. In contrast, VIP-IR fibres were only sparsely present, and SOM-IR was not detected...

  16. Progesterone-induced stimulation of mammary tumorigenesis is due to the progesterone metabolite, 5α-dihydroprogesterone (5αP) and can be suppressed by the 5α-reductase inhibitor, finasteride.

    Science.gov (United States)

    Wiebe, John P; Rivas, Martin A; Mercogliano, Maria F; Elizalde, Patricia V; Schillaci, Roxana

    2015-05-01

    Progesterone has long been linked to breast cancer but its actual role as a cancer promoter has remained in dispute. Previous in vitro studies have shown that progesterone is converted to 5α-dihydroprogesterone (5αP) in breast tissue and human breast cell lines by the action of 5α-reductase, and that 5αP acts as a cancer-promoter hormone. Also studies with human breast cell lines in which the conversion of progesterone to 5αP is blocked by a 5α-reductase inhibitor, have shown that the in vitro stimulation in cell proliferation with progesterone treatments are not due to progesterone itself but to the metabolite 5αP. No similar in vivo study has been previously reported. The objective of the current studies was to determine in an in vivo mouse model if the presumptive progesterone-induced mammary tumorigenesis is due to the progesterone metabolite, 5αP. BALB/c mice were challenged with C4HD murine mammary cells, which have been shown to form tumors when treated with progesterone or the progestin, medroxyprogesterone acetate. Cells and mice were treated with various doses and combinations of progesterone, 5αP and/or the 5α-reductase inhibitor, finasteride, and the effects on cell proliferation and induction and growth of tumors were monitored. Hormone levels in serum and tumors were measured by specific RIA and ELISA tests. Proliferation of C4HD cells and induction and growth of tumors was stimulated by treatment with either progesterone or 5αP. The progesterone-induced stimulation was blocked by finasteride and reinstated by concomitant treatment with 5αP. The 5αP-induced tumors expressed high levels of ER, PR and ErbB-2. Hormone measurements showed significantly higher levels of 5αP in serum from mice with tumors than from mice without tumors, regardless of treatments, and 5αP levels were significantly higher (about 4-fold) in tumors than in respective sera, while progesterone levels did not differ between the compartments. The results indicate that

  17. 4-Vinylcyclohexene Diepoxide (VCD) Inhibits Mammary Epithelial Differentiation and Induces Fibroadenoma Formation in Female Sprague Dawley Rats

    Science.gov (United States)

    Wright, Laura E.; Frye, Jennifer B.; Lukefahr, Ashley L.; Marion, Samuel L.; Hoyer, Patricia B.; Besselsen, David G.; Funk, Janet L.

    2011-01-01

    4-Vinylcyclohexene diepoxide (VCD), an occupational chemical that targets ovarian follicles and accelerates ovarian failure in rodents, was used to test the effect of early-onset reproductive senescence on mammary fibroadenoma formation. One-month female Sprague Dawley rats were dosed with VCD (80 mg/kg or 160 mg/kg) and monitored for 22 months for persistent estrus and tumor development. Only high-dose VCD treatment accelerated the onset of persistent estrus relative to controls. However, both doses of VCD accelerated mammary tumor onset by 5 months, increasing incidence to 84% (vs. 38% in controls). Tumor development was independent of time in persistent estrus, 17β-estradiol, androstenedione and prolactin. Delay in VCD administration until after completion of mammary epithelial differentiation (3 months) did not alter tumor formation despite acceleration of ovarian senescence. VCD administration to 1-month rats acutely decreased mammary alveolar bud number and expression of β-casein, suggesting that VCD’s tumorigenic effect requires exposure during mammary epithelial differentiation. PMID:21621605

  18. Chemopreventive Activity of Honokiol against 7, 12 - Dimethylbenz[a]anthracene-Induced Mammary Cancer in Female Sprague Dawley Rats

    Directory of Open Access Journals (Sweden)

    Zhenyu Wang

    2017-05-01

    Full Text Available Breast cancer is a predominant cause of death in women across the globe. Chemoprevention by using natural, dietary or synthetic products has been appearing to be a fascinating approach to combat the growing burden of breast cancer. In the current study, we intended to explore the mechanisms of chemopreventive action of honokiol against 7, 12 - dimethylbenz[a]anthracene (DMBA-induced mammary cancer in female Sprague Dawlely (SD rats. We induced mammary cancer in SD rats by administering single dose of DMBA (80 mg/kg through intra gastric route. Chemopreventive effects of honokiol (80 mg/kg, i.p. were confirmed from its ameliorating effect on the DMBA-induced anomalies such as liver marker enzymes, Phases I and II metabolizing enzymes and oxidative stress markers. Further, honokiol reversed the DMBA-induced abnormalities in inflammatory cytokines levels and serum tumor markers. Additionally, histopathological examination of mammary tissue and protein expression analysis of NF-κB revealed that honokiol is effective against DMBA-induced mammary cancer. In summary, the results of our study support the chemopreventive feature of honokiol in mammary cancer.

  19. Formation and persistence of DNA adducts from the carcinogen N-hydroxy-2-acetylaminofluorene in rat mammary gland in vivo

    International Nuclear Information System (INIS)

    Allaben, W.T.; Weis, C.C.; Fullerton, N.F.; Beland, F.A.

    1983-01-01

    The rat mammary carcinogen, N-hydroxy-2-acetylaminofluorene (N-hydroxy-2-AAF), has been proposed to be metabolically activated by mammary cytosolic N,O-acetyltransferase to a DNA binding species. To test this hypothesis, adult female Sprague-Dawley derived CD rats were treated, i.p., with 4.0 mg/kg [ring- 3 H]N-hydroxy-2-AAF. After 4 h, 1, 3, 14, and 28 days, the animals were killed, the mammary epithelium DNA was isolated and the carcinogen-deoxyribonucleoside adducts present were analyzed by high pressure liquid chromatography. At each time, only one adduct was detected and it was chromatographically identical to N-(deoxyguanosin-8-yl)-2-aminofluorene. The level of the adduct was maximal at 4 h (1.5 adducts/10(6) nucleotides) and then decreased, following first order kinetics with a t1/2 of 14.2 days. The detection of a single non-acetylated aminofluorene adduct is consistent with N,O-acyltransferase being involved in the metabolic activation of N-hydroxy-2-AAF in the rat mammary gland

  20. Gene expression profiling distinguishes between spontaneous and radiation-induced rat mammary carcinomas

    International Nuclear Information System (INIS)

    Imaoka, Tatsuhiko; Nishimura, Mayumi; Kakinuma, Shizuko; Shimada, Yoshiya; Yamashita, Satoshi; Ushijima, Toshikazu

    2008-01-01

    The ability to distinguish between spontaneous and radiation-induced cancers in humans is expected to improve the resolution of estimated risk from low dose radiation. Mammary carcinomas were obtained from Sprague-Dawley rats that were either untreated (n=45) or acutely γ-irradiated (1 Gy; n=20) at seven weeks of age. Gene expression profiles of three spontaneous and four radiation-induced carcinomas, as well as those of normal mammary glands, were analyzed by microarrays. Differential expression of identified genes of interest was then verified by quantitative polymerase chain reaction (qPCR). Cluster analysis of global gene expression suggested that spontaneous carcinomas were distinguished from a heterogeneous population of radiation-induced carcinomas, though most gene expressions were common. We identified 50 genes that had different expression levels between spontaneous and radiogenic carcinomas. We then selected 18 genes for confirmation of the microarray data by qPCR analysis and obtained the following results: high expression of Plg, Pgr and Wnt4 was characteristic to all spontaneous carcinomas; Tnfsf11, Fgf10, Agtr1a, S100A9 and Pou3f3 showed high expression in a subset of radiation-induced carcinomas; and increased Gp2, Areg and Igf2 expression, as well as decreased expression of Ca3 and noncoding RNA Mg1, were common to all carcinomas. Thus, gene expression analysis distinguished between spontaneous and radiogenic carcinomas, suggesting possible differences in their carcinogenic mechanism. (author)

  1. Effects of ionizing irradiation on the estradiol and progesterone receptors in rat mammary tumors

    International Nuclear Information System (INIS)

    Janssens, J.P.; Wittevrongel, C.; Van Dam, J.; Goddeeris, P.; Lauwerijns, J.M.; De Loecker, W.

    1981-01-01

    The determination of estradiol and progesterone receptor concentrations in mammary tumors is useful in predicting the hormone responsiveness. As this assay is carried out on tumor tissue which may have been subjected to radiotherapy, the possibility of an ionizing irradiation affecting the steroid receptor levels in neoplastic tissue should be taken into account. The steroid receptor concentrations are examined in dimethylbenz(a)anthracene-induced tumors os Sprague-Dawley rats. The estradiol and the progesterone receptor titers become reduced significantly after treatment with 20 Gray while an application with 7 Gray does not affect the titer values. After treatment of the tumor with 20 Gray, the steroid receptor concentrations decrease progressively, reaching a maximal reduction 20 to 30 days after exposure. As radiation treatment affects the receptor concentrations, this should be kept in mind when interpreting the steroid receptor concentrations

  2. Rat mammary-cell survival following irradiation with 14.3-MeV neutrons

    International Nuclear Information System (INIS)

    Mahler, P.A.; Gould, M.N.; DeLuca, P.M. Jr.; Pearson, D.W.; Clifton, K.H.

    1982-01-01

    The survival of rat mammary gland cells irradiated in situ with either single or split doses of 14.3-MeV neutrons was determined by an in vivo transplantation assay. The single-dose data are best fit to the multitarget single-hit model by the parameters D 0 = 97 cGy and n = 0.6 while the split-dose data are best fit by the parameters D 0 = 100 cGy and n = 1.2. Analysis of the combined data sets suggests that the two survival curves are not identical. Comparison of these data with previously published results following irradiation with 250-kVp x-rays is reported

  3. Rat mammary cell survival following irradiation with 14.3-MeV neutrons

    International Nuclear Information System (INIS)

    Mahler, P.A.; Gould, M.N.; DeLuca, P.M. Jr.; Pearson, D.W.; Clifton, K.H.

    1982-01-01

    The survival of rat mammary gland cells irradiated in situ with either single or split doses of 14.3-MeV neutrons was determined by an in vivo transplantation assay. The single-dose data are best fit to the multitarget single-hit model by the parameters D/sub o/ = 97 cGy and n = 0.6 while the split-dose data are best fit by the parameters D/sub o/ = 100 cGy and n = 1.2.Analysis of the combined data sets suggests that the two survival curves are not identical. Comparison of these data with previously published results following irradiation with 250-kVp X rays is reported

  4. BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors

    International Nuclear Information System (INIS)

    Samuelson, Emma; Karlsson, Sara; Partheen, Karolina; Nilsson, Staffan; Szpirer, Claude; Behboudi, Afrouz

    2012-01-01

    Development of breast cancer is a multistage process influenced by hormonal and environmental factors as well as by genetic background. The search for genes underlying this malignancy has recently been highly productive, but the etiology behind this complex disease is still not understood. In studies using animal cancer models, heterogeneity of the genetic background and environmental factors is reduced and thus analysis and identification of genetic aberrations in tumors may become easier. To identify chromosomal regions potentially involved in the initiation and progression of mammary cancer, in the present work we subjected a subset of experimental mammary tumors to cytogenetic and molecular genetic analysis. Mammary tumors were induced with DMBA (7,12-dimethylbenz[a]anthrazene) in female rats from the susceptible SPRD-Cu3 strain and from crosses and backcrosses between this strain and the resistant WKY strain. We first produced a general overview of chromosomal aberrations in the tumors using conventional kartyotyping (G-banding) and Comparative Genome Hybridization (CGH) analyses. Particular chromosomal changes were then analyzed in more details using an in-house developed BAC (bacterial artificial chromosome) CGH-array platform. Tumors appeared to be diploid by conventional karyotyping, however several sub-microscopic chromosome gains or losses in the tumor material were identified by BAC CGH-array analysis. An oncogenetic tree analysis based on the BAC CGH-array data suggested gain of rat chromosome (RNO) band 12q11, loss of RNO5q32 or RNO6q21 as the earliest events in the development of these mammary tumors. Some of the identified changes appear to be more specific for DMBA-induced mammary tumors and some are similar to those previously reported in ACI rat model for estradiol-induced mammary tumors. The later group of changes is more interesting, since they may represent anomalies that involve genes with a critical role in mammary tumor development. Genetic

  5. Altered expression of glycosaminoglycans in metastatic 13762NF rat mammary adenocarcinoma cells

    International Nuclear Information System (INIS)

    Steck, P.A.; Cheong, P.H.; Nakajima, M.; Yung, W.K.A.; Moser, R.P.; Nicolson, G.L.

    1987-01-01

    A difference in the expression and metabolism of [ 35 S]sulfated glycosaminoglycans between rat mammary tumor cells derived from a primary tumor and those from its metastatic lesions has been observed. Cells from the primary tumor possessed about equal quantities of chondroitin sulfate and heparan sulfate on their cell surfaces but released fourfold more chondroitin sulfate than heparan sulfate into their medium. In contrast, cells from distal metastatic lesions expressed approximately 5 times more heparan sulfate than chondroitin sulfate in both medium and cell surface fractions. This was observed to be the result of differential synthesis of the glycosaminoglycans and not of major structural alterations of the individual glycosaminoglycans. The degree of sulfation and size of heparan sulfate were similar for all cells examined. However, chondroitin sulfate, observed to be only chondroitin 4-sulfate, from the metastases-derived cells had a smaller average molecular weight on gel filtration chromatography and showed a decreased quantity of sulfated disaccharides upon degradation with chondroitin ABC lyase compared to the primary tumor derived cells. Major qualitative or quantitative alterations were not observed for hyaluronic acid among the various 13762NF cells. The metabolism of newly synthesized sulfated glycosaminoglycans was also different between cells from primary tumor and metastases. A pulse-chase kinetics study demonstrated that both heparan sulfate and chondroitin sulfate were degraded by the metastases-derived cells, whereas the primary tumor derived cells degraded only heparan sulfate and degraded it at a slower rate. These results suggested that altered glycosaminoglycan expression and metabolism may be associated with the metastatic process in 13762NF rat mammary tumor cells

  6. Influence of long-term treatment of the rat with clebopride on the morphology of the mammary gland.

    Science.gov (United States)

    de Lima, T C; Morato, G S; Loch, S; Tames, D R

    1990-01-01

    The substituted benzamides or orthopramides are used to treat gastrointestinal and psychotic disorders. The orthopramide clebopride, a potent dopaminergic antagonist, blocks emesis in dogs and stereotyped behavior in rodents. Since the release of prolactin is inhibited by dopamine, antidopaminergic drugs may be useful to increase lactation in nursing mothers. The present work examines the morphological and histological alterations produced by long-term treatment of puerperal and virgin female rats with clebopride. Clebopride induced significant hyperplasia of parenchymal secretory units and stimulated milk secretion in both groups of rats. However, only in virgin rats was mammary weight significantly increased.

  7. In utero and lactational exposure to vinclozolin and genistein induces genomic changes in the rat mammary gland.

    Science.gov (United States)

    El Sheikh Saad, H; Toullec, A; Vacher, S; Pocard, M; Bieche, I; Perrot-Applanat, M

    2013-02-01

    Exposure to low doses of environmental estrogens such as bisphenol A and genistein (G) alters mammary gland development. The effects of environmental anti-androgens, such as the fungicide vinclozolin (V), on mammary gland morphogenesis are unknown. We previously reported that perinatal exposure to G, V, and the GV combination causes histological changes in the mammary gland during the peripubertal period, suggesting alterations to the peripubertal hormone response. We now investigate whether perinatal exposure to these compounds alters the gene expression profiles of the developing glands to identify the dysregulated signaling pathways and the underlying mechanisms. G, V, or GV (1 mg/kg body weight per day) was added to diet of Wistar rats, from conception to weaning; female offspring mammary glands were collected at postnatal days (PNDs) 35 and 50. Genes displaying differential expression and belonging to different functional categories were validated by quantitative PCR and immunocytochemistry. At PND35, G had little effect; the slight changes noted were in genes related to morphogenesis. The changes following exposure to V concerned the functional categories associated with development (Cldn1, Krt17, and Sprr1a), carbohydrate metabolism, and steroidogenesis. The GV mixture upregulated genes (Krt17, Pvalb, and Tnni2) involved in muscle development, indicating effects on myoepithelial cells during mammary gland morphogenesis. Importantly, at PND50, cycling females exposed to GV showed an increase in the expression of genes (Csn2, Wap, and Elf5) related to differentiation, consistent with the previously reported abnormal lobuloalveolar development previously described. Thus, perinatal exposure to GV alters the mammary gland hormone response differently at PND35 (puberty) and in animals with established cycles.

  8. In vivo mammary tumourigenesis in the Sprague-Dawley rat and microdosimetric correlates

    International Nuclear Information System (INIS)

    Dicello, J F; Christian, A; Cucinotta, F A

    2004-01-01

    Standard methods for risk assessments resulting from human exposures to mixed radiation fields in Space consisting of different particle types and energies rely upon quality factors. These are generally defined as a function of linear energy transfer (LET) and are assumed to be proportional to the risk. In this approach, it is further assumed that the risks for single exposures from each of the radiation types add linearly. Although risks of cancer from acute exposures to photon radiations have been measured in humans, quality factors for protons and ions of heavier atomic mass are generally inferred from animal and/or cellular data. Because only a small amount of data exists for such particles, this group has been examining tumourigenesis initiated by energetic protons and iron ions. In this study, 741 female Sprague-Dawley rats were irradiated or sham irradiated at approximately 60 days of age with 250 MeV protons, 1 GeV/nucleon iron ions or both protons and iron ions. The results suggest that the risk of mammary tumours in the rats sequentially irradiated with 1 GeV/nucleon 56 Fe ions and 250 MeV protons is less than additive. These data in conjunction with earlier results further suggest that risk assessments in terms of only mean LETs of the primary cosmic rays may be insufficient to accurately evaluate the relative risks of each type of particle in a radiation field of mixed radiation qualities

  9. The plasticizer butyl benzyl phthalate induces genomic changes in rat mammary gland after neonatal/prepubertal exposure

    Directory of Open Access Journals (Sweden)

    Lamartiniere Coral A

    2007-12-01

    Full Text Available Abstract Background Phthalate esters like n-butyl benzyl phthalate (BBP are widely used plasticizers. BBP has shown endocrine-disrupting properties, thus having a potential effect on hormone-sensitive tissues. The aim of this study is to determine the effect of neonatal/prepubertal exposure (post-natal days 2–20 to BBP on maturation parameters and on the morphology, proliferative index and genomic signature of the rat mammary gland at different ages of development (21, 35, 50 and 100 days. Results Here we show that exposure to BBP increased the uterine weight/body weight ratio at 21 days and decreased the body weight at time of vaginal opening. BBP did not induce significant changes on the morphology of the mammary gland, but increased proliferative index in terminal end buds at 35 days and in lobules 1 at several ages. Moreover, BBP had an effect on the genomic profile of the mammary gland mainly at the end of the exposure (21 days, becoming less prominent thereafter. By this age a significant number of genes related to proliferation and differentiation, communication and signal transduction were up-regulated in the glands of the exposed animals. Conclusion These results suggest that BBP has an effect in the gene expression profile of the mammary gland.

  10. The Effect of Tamoxifen Administration and γ-Irradiation on Thyroid Hormones Levels in Rats Bearing Mammary Tumours

    International Nuclear Information System (INIS)

    Abdelgawad, M.R.

    2013-01-01

    Breast Cancer is the most common malignancy among women in most developed and developing regions of the world, in female, tamoxifen acting as an oestrogen antagonist on the breast. Thyroid hormones can stimulate the proliferation in vitro of certain tumor cell lines. The aim of the present study is to evaluate the effect of tamoxifen and/ or irradiation treatment on thyroid hormones in rats' mammary tumours. Forty-two female Sprague-Dawely rats randomly divided into seven groups' proliferation (6 rats each). Control group, normal rats supplemented with tamoxifen for 3 weeks, normal rats exposed to a single dose 3Gy γ-rays, rats treated with Dimethylbenz (a) anthracene (DMBA) dissolved in corn oil (30ppm) sc and followed for 6 months until breast cancer occurrence, breast cancer bearing rats supplemented with tamoxifen for 3 weeks twice a day, breast cancer bearing rats exposed to a single dose 3Gy γ-rays, breast cancer bearing rats exposed to a single dose 3Gy γ-rays and supplemented with tamoxifen for 3 weeks twice a day. At the end of the experiment, mammary tumours and control rats were sacrificed after 3 weeks from different treatments and serum thyroid hormones and estradiol (E2) levels were assayed using commercial kits. Results show T4 and E2 levels not triiodothyronine (T3) were altered in different experimental groups. It could be concluded that γ-irradiation promote the expression of neoplastic potential by affecting both E2 and thyroid hormones and tamoxifen may alter the thyroid hormones. Tamoxifen administration and γ-irradiation may have worth effects on thyroxin (T4) and E2 levels. It is recommended to further studies towards the bystander effect of γ-rays exposure and tamoxifen treatment on the tissue culture and molecular biology scale.

  11. Isolation and characterization of proteins of the mouse mammary tumour virus

    International Nuclear Information System (INIS)

    Westenbrink, F.

    1980-01-01

    A vaccination procedure was developed to mouse mammary tumor virus (MuMTV) induced mouse mammary tumorigenesis. The structural proteins of MuMTV were purified so that their immunogenic qualities were retained. Radioimmunoassays were developed for the proteins. (Auth.)

  12. Ethanol-Extracted Brazilian Propolis Exerts Protective Effects on Tumorigenesis in Wistar Hannover Rats.

    Directory of Open Access Journals (Sweden)

    Anna Kakehashi

    Full Text Available The present study was conducted over a course of 104 weeks to estimate the carcinogenicity of ethanol-extracted Brazilian green propolis (EEP. Groups of 50 male and 50 female Wistar Hannover rats, 6-week-old at commencement were exposed to EEP at doses of 0, 0.5 or 2.5% in the diet. Survival rates of 0.5% and 2.5% EEP-treated male and female rats, respectively, were significantly higher than those of respective control groups. Overall histopathological evaluation of neoplasms in rat tissues after 2 years showed no significant increase of tumors or preneoplastic lesions in any organ of animals administered EEP. Significantly lower incidences of pituitary tumors in 0.5% EEP male and 2.5% EEP female groups, malignant lymphoma/leukemia in both 2.5% EEP-treated males and females and total thyroid tumors in 0.5% EEP male group were found. Administration of EEP caused significant decreases of lymphoid hyperplasia of the thymus and lymph nodes in 2.5% EEP-treated rats, tubular cell hyperplasia of kidneys in all EEP groups, and cortical hyperplasia of adrenals in EEP-treated females. In the blood, significant reduction of neutrophils in all EEP-treated males and band neutrophils in 2.5% EEP-treated females was found indicating lower levels of inflammation. Total cholesterol and triglicerides levels were significantly lower in the blood of 2.5% EEP-treated female rats. In conclusion, under the conditions of the 2-year feeding experiment, EEP was not carcinogenic, did not induce significant histopathological changes in any organ, and further exerted anti-inflammatory and antitumorigenic effects resulting in increase of survival of Wistar Hannover rats.

  13. Calcitonin-like immunoreactivity and calcitonin gene expression in the placenta and in the mammary gland of the rat

    Energy Technology Data Exchange (ETDEWEB)

    Jousset, V; Legendre, B; Besnard, P; Segond, N; Jullienne, A

    1988-01-01

    Recently, the presence of monomeric CT in plasma and milk was reported by others in a lactating woman surgically thyroidectomized. Similarly, the placenta was thought to be a possible source of CT. Since such findings were based exclusively on immunological arguments, we have investigated the CT gene expression in these rat tissues. CT mRNAs were detected by dot-blot hybridization of total RNAs extracted from rat tissues with a /sup 32/P-labelled human CT cDNa probe. Subcellular fractions of each tissue were screened for CT-like immunoreactivity using two different antibodies. With one antibody, extracts of the mammary gland and placenta both produced full displacement of labelled human CT from the antiserum and serial dilutions of the extracts gave displacement curves parallel to that of synthetic human CT, which suggests immunological similarity. However, dilution curves were not parallel for the second antibody, and for both antisera, CT-like immunoreactivity was found in all subsellular fractions from nuclei to cytosols. Immunoprecipitation of translation products from poly (A)/sup +/RNAs of placenta showed two major bands around 30 kD. Under stringent conditions, the weak hybridization of placental RNAs seen by dot-blot under less stringent conditions disappeared. Northern analyses of total RNAs from the placenta failed to detect mRNA of 1 k base size like in thyroid glands, but hybridization under weak stringent conditions occurred with larger mRNAs (around 4.4 and 2.4 k bases). Immunoprecipitation of translation products from mRNAs of rat mammary glands showed three major bands around 46, 30 and 20 kD. Our results suggest that the CT gene is not expressed in the rat placenta and in rat mammary gland, since CT mRNAs were not detected in either tissues. (EB).

  14. A study on the radiation effect on microvasculature of N-methyl-N-Nitrosourea-induced mammary carcinoma in rats

    International Nuclear Information System (INIS)

    Bae, Sang Hoon; Koh, Kyoung Hwan; Im, Chung Kie; Ha, Sung Hwan; Han, Man Chung

    1985-01-01

    Mammary carcinoma was induced in rats by intravenous injection of N-methyl-N-Nitrosourea. Microangiography was performed to evaluate the microvascular alterations in mammary carcinoma after irradiation. The tumors were given a single dose of 1,400 rads using Co-60 teletherapy unit with field size of 4 x 4 cm at 40 cm SSD. The dose rate was 147.5 rads per minute. Microangiography was performed prior to irradiation and at one, two, and four weeks following irradiation. The results are as follows: 1. Before irradiation, mammary carcinoma in rats tended to form lobules and the basic vasculature consisted of peripheral vascular pattern with central penetrating vessels. The peripheral vascular pattern was always richer than that of the center. Irregular and tortuous vessels stretched from the periphery into the center of lobule. 2. One week following irradiation, an increase in the number of smaller, tortuous vessels and decreased intervascular distance were observed in the central portion of each lobule. This finding seems to be due to an improved filling of some previously existing but unfilled vessels. This may lead to improved metabolic changes and reoxygenation. 3. Later changes of microvasculature after irradiation are tortuosity, irregularity, narrowing, abrupt tapering, fragmentation, and extravasation. These findings progressed after a lapse of time. 4. The results can be considered as the microangiographic demonstration of the fact that reoxygenation after irradiation is mainly due to dilatation of the collapsed tumor vessels

  15. The effect of isoprenaline on induction of tumours by methyl nitrosourea in the salivary and mammary glands of female wistar rats.

    Science.gov (United States)

    Parkin, R.; Neale, S.

    1976-01-01

    Pretreatment of rats with isoprenaline sulphate (IPR) stimulated DNA synthesis in both salivary and mammary gland tissues. Salivary gland tumours induced by N-methyl-N-nitrosourea (MNU) were observed for the first time in rats, but occurred only in IPR-pretreated animals given MNU during the period of IPR-stimulated DNA synthesis. The cumulative index of MNU-induced mammary tumours and the number of tumours per tumour-bearing rat were increased by IPR-pretreament only if the animals received MNU during the period of IPR-stimulated DNA synthesis. PMID:974007

  16. Radiation resistance in a melphalan-resistant subline of a rat mammary carcinoma

    International Nuclear Information System (INIS)

    Lehnert, S.; Vestergaard, J.; Batist, G.; Aloui-Jamali, M.A.

    1994-01-01

    A subline of a rat mammary carcinoma (MATB 13762), selected for resistance to melphalan, is cross-resistant to other alkylating drugs, to unrelated drugs and to ionizing radiation. The difference in radioresponse between the sensitive wild-type cell line and the melphalan- and radiation-resistant line (MLN r ) is related to the size of the α component in the linear-quadratic model. Reduction of dose rate does not affect the response of MLN r cells but does increase survival for wild-type cells. MLN r cells have elevated levels of reduced glutathione (GSH) and overexpress redox enzymes glutathione-S-transferase and glutathione peroxidase. Modest depletion of GSH (to 50% of control) radiosensitizes MLN r cells but not wild-type cells. On the basis of the results of an excitation assay, growth delay and tumor control experiments, MATB MLN r tumors are also more radioresistant than wild-type cells when irradiated in situ. However, wild-type cells irradiated shortly after excision of the tumor are much more radioresistant than the same cells irradiated 24 h after excision or maintained in culture, and their response resembles that of MLN r cells irradiated under the same conditions. These results suggest that, in spite of some similarity between the in vivo and in vitro observations, intrinsic radioresistance is not the most important factor influencing the response of MLN r cells in vivo. 22 refs., 7 figs., 4 tabs

  17. Taurine Attenuates Dimethylbenz[a]anthracene-induced Breast Tumorigenesis in Rats: A Plasma Metabolomic Study.

    Science.gov (United States)

    He, Y U; Li, Qingdi Quentin; Guo, Song Chao

    2016-02-01

    Breast cancer is the most common malignancy and the leading cause of cancer-related mortality in women worldwide. Taurine, the most abundant free amino acid, plays a role in several biological processes in humans and has been shown to have activity against breast cancer and other tumors. To investigate the role and mechanism of taurine action in breast cancer, we used dimethylbenz[a]anthracene (DMBA)-induced breast carcinogenesis in rats as a model of breast cancer. The administration of taurine significantly reduced the DMBA-induced breast cancer rate from 80% to 40% in rats (ptaurine-administered rats. Bioinformatic analysis further revealed that these metabolites are involved in multiple metabolic pathways, including energy, glucose, amino acid, and nucleic acid metabolism, suggesting that the antitumor activity of taurine in rats is mediated through altered metabolism of breast cancer cells. We propose that these differential metabolites may be potential biomarkers for monitoring cancer therapy and prognosis in the clinic. This study provides a scientific basis for further investigations of the antitumor mechanism of taurine and the development of novel therapeutic strategies to treat breast cancer. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  18. Mammary carcinogenesis induced by three consecutive 14 MeV neutron irradiations in Sprague-Dawley rats

    International Nuclear Information System (INIS)

    Jacrot, M.; Mouriquand, J.; Mouriquand, C.

    1978-01-01

    At high doses (400 to 800 rads) the relative biological effectiveness (R.B.E.) of neutrons is two or three times greater than that of X-rays or gamma radiation. The neutron irradiation-induced mammary carcinogenesis threshold, if any, is certainly very low in Sprague-Dawley females. The purpose of this work is to test the possibilities offered by three consecutive 14 MeV neutron irradiations in the mammary carcinogenesis region of Sprague-Dawley rats. The results of these experiments show a hormone-dependence of tumour promotion similar to that observed with chemical carcinogenetic agents. However these tumours, by their recurrences and possible metastases, bear some resemblance to breast cancers in women. Although the tumour induction frequencies seem modest in relation to those obtained with the DMBA model they should nevertheless prove very useful in the study of hormone effects liable to control the appearance of such radioinduced cancers [fr

  19. Effects of grafts of single anterior pituitary glands on the incidence and type of mammary neoplasm in neutron- or γ-irradiated Fischer female rats

    International Nuclear Information System (INIS)

    Clifton, K.H.; Douple, E.B.; Sridharan, B.N.

    1976-01-01

    Three batches comprised of 48 young adult Fischer female rats each were subjected to total-body irradiation with 50 rads modified fission neutrons, or were given 600 rads 137 Cs γ-rays, or served as unirradiated controls. On the day following exposure, one-half of each batch was grafted with a single anterior pituitary gland beneath the left kidney capsule. The animals were observed for mammary neoplasia and all those that died during the experiment were autopsied. The experiment was terminated 538 +- 13 days after irradiation when all neutron-irradiated, pituitary-grafted animals had one or more mammary tumors. Only 2 of the 23 untreated rats that survived until termination of the experiment developed mammary fibroadenomas, and none had mammary carcinomas. The incidence of fibroadenomas was increased, and a single carcinoma was found in unirradiated rats with pituitary grafts. Irradiation alone caused an increase in the incidence of mammary fibroadenomas and the appearance of carcinomas. Fibroadenomas were markedly increased by the addition of pituitary grafts to irradiation. Carcinoma incidence was less markedly affected. The neutron dose of 50 rads was slightly more effective in inducing mammary neoplasms than the 600-rad dose of γ-rays

  20. Early-in-life dietary zinc deficiency and supplementation and mammary tumor development in adulthood female rats.

    Science.gov (United States)

    da Silva, Flávia R M; Grassi, Tony F; Zapaterini, Joyce R; Bidinotto, Lucas T; Barbisan, Luis F

    2017-06-01

    Zinc deficiency during pregnancy and postnatal life can adversely increase risk of developing human diseases at adulthood. The present study was designed to evaluate whether dietary zinc deficiency or supplementation during the pregnancy, lactation and juvenile stages interferes in the development of mammary tumors induced by 7,12-dimethylbenzanthracene (DMBA) in female Sprague-Dawley (SD) rats. Pregnant female SD rats were allocated into three groups: zinc-adequate diet (ZnA - 35-mg/kg chow), zinc-deficient diet (ZnD - 3-mg/kg chow) or zinc-supplemented diet (ZnS - 180-mg/kg chow) during gestational day 10 (GD 10) until the litters' weaning. Female offspring received the same diets as their dams until postnatal day (PND) 51. At PND 51, the animals received a single dose of DMBA (50 mg/kg, ig) and zinc-adequate diets. At PND 180, female were euthanized, and tumor samples were processed for histological evaluation and gene expression microarray analysis. The ZnD induced a significant reduction in female offspring body weight evolution and in mammary gland development. At late in life, the ZnD or ZnS did not alter the latency, incidence, multiplicity, volume or histological types of mammary tumors in relation to the ZnA group. However, the total tumor number in ZnS group was higher than in ZnA group, accompanied by distinct expression of 4 genes up- and 15 genes down-regulated. The present findings indicate that early-in-life dietary zinc supplementation, differently to zinc deficiency, has a potential to modify the susceptibility to the development of mammary tumors induced by DMBA. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Rat models of 17β-estradiol-induced mammary cancer reveal novel insights into breast cancer etiology and prevention.

    Science.gov (United States)

    Shull, James D; Dennison, Kirsten L; Chack, Aaron C; Trentham-Dietz, Amy

    2018-03-01

    Numerous laboratory and epidemiologic studies strongly implicate endogenous and exogenous estrogens in the etiology of breast cancer. Data summarized herein suggest that the ACI rat model of 17β-estradiol (E2)-induced mammary cancer is unique among rodent models in the extent to which it faithfully reflects the etiology and biology of luminal types of breast cancer, which together constitute ~70% of all breast cancers. E2 drives cancer development in this model through mechanisms that are largely dependent upon estrogen receptors and require progesterone and its receptors. Moreover, mammary cancer development appears to be associated with generation of oxidative stress and can be modified by multiple dietary factors, several of which may attenuate the actions of reactive oxygen species. Studies of susceptible ACI rats and resistant COP or BN rats provide novel insights into the genetic bases of susceptibility and the biological processes regulated by genetic determinants of susceptibility. This review summarizes research progress resulting from use of these physiologically relevant rat models to advance understanding of breast cancer etiology and prevention.

  2. Enhancement of skin tumorigenesis by cigarette smoke condensate following beta-irradiation in rats

    International Nuclear Information System (INIS)

    McGregor, J.F.

    1982-01-01

    The tumor-promoting ability of cigarette-smoke condensate (CSC) has been demonstrated in rat skin after beta-irradiation. Skin tumors from male albino Charles River CD rats (outbred Sprague-Dawley descended) were classified into 2 groups: carcinomas and other noncarcinoma tumors. A statistically significant increase (P less than 0.01) in tumor yield occurred after CSC treatment that began 2 months after irradiation. This finding confirmed our previously published pilot observation. Extension of the pilot experiment to obtain data on carcinoma yield and an experiment to observe the effects of CSC treatment beginning immediately after irradiation were performed. When CSC treatment began immediately after irradiation, the yield of noncarcinoma tumors was significantly reduced (P less than 0.01), whereas the carcinoma yield increased but statistically not significantly (P . 0.12). The increased yield of noncarcinoma tumors is attributed to a significant increase (P less than 0.01) of acute ulceration caused by CSC on recently irradiated skin. The increase in carcinoma yield resulted from an increase in the rate of conversion of noncarcinoma tumors to cancer. Carcinoma yield was also increased by CSC treatment beginning 2 months after irradiation, but the increase was not significant (P . 0.08). The lack of statistical significance for the carcinoma yields in both experiments may be ascribed to the insufficient number of cancers produced by the treatments. The relative ratios of cancer yields (1.7 and 2.5) did not differ greatly from the 2.2 ratio for the increase of noncarcinoma tumors. The possible relevance of the findings to human carcinogenesis is discussed

  3. Dose-rate effects for mammary tumor development in female Sprague-Dawley rats exposed to X and γ radiation

    International Nuclear Information System (INIS)

    Johnson, J.R.; Gragtmans, N.J.; Myers, D.K.; Jones, A.R.

    1989-01-01

    Mammary tumour development was followed in two experiments involving a total of 2229 female Sprague-Dawley rats exposed to various doses of X or γ rays at different dose rates. The data for another 462 rats exposed to tritiated water in one of these experiments were also analyzed. The incidence of adenocarcinomas and fibroadenomas at a given time after exposure increased linearly in proportion to total radiation dose for most groups. However, no significant increase in adenocarcinomas was observed with chronic γ exposures up to 1.1 Gy, and the increase in fibroadenomas observed with chronic gamma exposures at a dose rate of 0.0076 Gy h -1 up to an accumulated dose of 3.3 Gy was small compared to that observed after acute exposures. The incidence of all mammary tumors increased almost linearly with the log of dose rate in the range 0.0076 to 26.3 Gy h -1 for 3 Gy total dose of gamma rays. The effects of X rays appeared to be less influenced by dose rate than were the effects of γ rays. (author)

  4. Effects of radiation of cells in vivo: a rat mammary gland model

    International Nuclear Information System (INIS)

    Gould, M.N.

    1977-01-01

    A methodology has been developed for the quantitative transplantation of monodispersed mammary cells. When adequate numbers of cells are transplanted, normal functional mammary tissue containing both secretory and myoepithelial cells in their normal tissue locations is formed. The analysis of the shape of cell dose-transplantation curves indicates a single cell origin of this tissue. Quantitative transplantation data from density gradient separated mammary cell subpopulations indicate that this cell is not of a unique type. With the use of an assay based on development of such structures from inoculated cells, in vivo radiation dose-cell survival curves have been generated under two hormonal conditions which result in differing rates of cell proliferation in the mammary gland. Survival curves generated under hormonal states that result in slow and rapid mammary cell proliferation are superimposable. In these assays tissue was removed immediately after irradiation for transplantation. If, however, the cells (slowly proliferating) are allowed to remain in situ for 24 hrs before removal for transplantation, the value of D 0 remains the same while n and D/sub q/ increase. Evidence is presented that indicates that these changes are due to a unique component of the repair of radiation damage which is dependent on the retention of the cells in their in situ tissue environment following the radiation period. This repair process is termed in situ repair

  5. Homology analyses of the protein sequences of fatty acid synthases from chicken liver, rat mammary gland, and yeast

    International Nuclear Information System (INIS)

    Chang, Soo-Ik; Hammes, G.G.

    1989-01-01

    Homology analyses of the protein sequences of chicken liver and rat mammary gland fatty acid synthases were carried out. The amino acid sequences of the chicken and rat enzymes are 67% identical. If conservative substitutions are allowed, 78% of the amino acids are matched. A region of low homologies exists between the functional domains, in particular around amino acid residues 1059-1264 of the chicken enzyme. Homologies between the active sites of chicken and rat and of chicken and yeast enzymes have been analyzed by an alignment method. A high degree of homology exists between the active sites of the chicken and rat enzymes. However, the chicken and yeast enzymes show a lower degree of homology. The DADPH-binding dinucleotide folds of the β-ketoacyl reductase and the enoyl reductase sites were identified by comparison with a known consensus sequence for the DADP- and FAD-binding dinucleotide folds. The active sites of all of the enzymes are primarily in hydrophobic regions of the protein. This study suggests that the genes for the functional domains of fatty acid synthase were originally separated, and these genes were connected to each other by using different connecting nucleotide sequences in different species. An alternative explanation for the differences in rat and chicken is a common ancestry and mutations in the joining regions during evolution

  6. Prenatal exposure to BPA alters the epigenome of the rat mammary gland and increases the propensity to neoplastic development.

    Directory of Open Access Journals (Sweden)

    Eugen Dhimolea

    Full Text Available Exposure to environmental estrogens (xenoestrogens may play a causal role in the increased breast cancer incidence which has been observed in Europe and the US over the last 50 years. The xenoestrogen bisphenol A (BPA leaches from plastic food/beverage containers and dental materials. Fetal exposure to BPA induces preneoplastic and neoplastic lesions in the adult rat mammary gland. Previous results suggest that BPA acts through the estrogen receptors which are detected exclusively in the mesenchyme during the exposure period by directly altering gene expression, leading to alterations of the reciprocal interactions between mesenchyme and epithelium. This initiates a long sequence of altered morphogenetic events leading to neoplastic transformation. Additionally, BPA induces epigenetic changes in some tissues. To explore this mechanism in the mammary gland, Wistar-Furth rats were exposed subcutaneously via osmotic pumps to vehicle or 250 µg BPA/kg BW/day, a dose that induced ductal carcinomas in situ. Females exposed from gestational day 9 to postnatal day (PND 1 were sacrificed at PND4, PND21 and at first estrus after PND50. Genomic DNA (gDNA was isolated from the mammary tissue and immuno-precipitated using anti-5-methylcytosine antibodies. Detection and quantification of gDNA methylation status using the Nimblegen ChIP array revealed 7412 differentially methylated gDNA segments (out of 58207 segments, with the majority of changes occurring at PND21. Transcriptomal analysis revealed that the majority of gene expression differences between BPA- and vehicle-treated animals were observed later (PND50. BPA exposure resulted in higher levels of pro-activation histone H3K4 trimethylation at the transcriptional initiation site of the alpha-lactalbumin gene at PND4, concomitantly enhancing mRNA expression of this gene. These results show that fetal BPA exposure triggers changes in the postnatal and adult mammary gland epigenome and alters gene

  7. Mammary stem cells: angels or demons in mammary gland?

    Science.gov (United States)

    Chen, Xueman; Liu, Qiang; Song, Erwei

    2017-01-01

    A highly dynamic development process exits within the epithelia of mammary gland, featuring morphogenetic variation during puberty, pregnancy, lactation, and regression. The identification of mammary stem cells (MaSCs) via lineage-tracing studies has substantiated a hierarchical organization of the mammary epithelia. A single MaSC is capable of reconstituting the entirely functional mammary gland upon orthotopic transplantation. Although different mammary cell subpopulations can be candidate cells-of-origin for distinct breast tumor subtypes, it still lacks experimental proofs whether MaSCs, the most primitive cells, are the 'seeds' of malignant transformation during most, if not all, tumorigenesis in the breast. Here, we review current knowledge of mammary epithelial hierarchy, highlighting the roles of mammary stem/progenitor cells and breast cancer stem cells (BCSCs) along with their key molecular regulators in organ development and cancer evolution. Clarifying these issues will pave the way for developing novel interventions toward stem/progenitor cells in either prevention or treatment of breast cancer (BrCa).

  8. Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus (QTL30 on rat chromosome 12: identification of fry as a candidate Mcs gene.

    Directory of Open Access Journals (Sweden)

    Xuefeng Ren

    Full Text Available Rat strains differ dramatically in their susceptibility to mammary carcinogenesis. On the assumption that susceptibility genes are conserved across mammalian species and hence inform human carcinogenesis, numerous investigators have used genetic linkage studies in rats to identify genes responsible for differential susceptibility to carcinogenesis. Using a genetic backcross between the resistant Copenhagen (Cop and susceptible Fischer 344 (F344 strains, we mapped a novel mammary carcinoma susceptibility (Mcs30 locus to the centromeric region on chromosome 12 (LOD score of ∼8.6 at the D12Rat59 marker. The Mcs30 locus comprises approximately 12 Mbp on the long arm of rat RNO12 whose synteny is conserved on human chromosome 13q12 to 13q13. After analyzing numerous genes comprising this locus, we identified Fry, the rat ortholog of the furry gene of Drosophila melanogaster, as a candidate Mcs gene. We cloned and determined the complete nucleotide sequence of the 13 kbp Fry mRNA. Sequence analysis indicated that the Fry gene was highly conserved across evolution, with 90% similarity of the predicted amino acid sequence among eutherian mammals. Comparison of the Fry sequence in the Cop and F344 strains identified two non-synonymous single nucleotide polymorphisms (SNPs, one of which creates a putative, de novo phosphorylation site. Further analysis showed that the expression of the Fry gene is reduced in a majority of rat mammary tumors. Our results also suggested that FRY activity was reduced in human breast carcinoma cell lines as a result of reduced levels or mutation. This study is the first to identify the Fry gene as a candidate Mcs gene. Our data suggest that the SNPs within the Fry gene contribute to the genetic susceptibility of the F344 rat strain to mammary carcinogenesis. These results provide the foundation for analyzing the role of the human FRY gene in cancer susceptibility and progression.

  9. [Effect of veralipride on the estral cycle, genital tract, mammary gland and pituitary gland in female rats (author's transl)].

    Science.gov (United States)

    Tuchmann-Duplessis, H

    1980-10-15

    A study of the potential biological effects of veralipride was conducted in female rats. A definite stimulating action on the mammary gland was noted, but doses of 5 to 20 mg/kg/day are required to produce secretion, which is varying from one animal to another. Follicular maturation is preserved, though there is an increase in the number of corpora lutea with more marked development in some of them. Progesterone impregnation of the uterus occurs in a variable way and then only at doses of 5 + 0 20 mg/kg/day. Vaginal mucification, from a reduction in estrogen in relation to progesterone impregnation, is noted after 1 mg/kg/day (though 25 p. cent of the animals still demonstrate vaginal keratinization after 20 mg/kg/day). Finally, degranulation of the carminophile cells of the anterior pituitary gland, occurs after 5 mg/kg/day.

  10. Effect of primrose oil and corn oil diets on eicosanoid synthesis by rat mammary tumor induced by dimethylbenzanthracene (DMBA)

    Energy Technology Data Exchange (ETDEWEB)

    El-Ela, S.H.A.; Bunce, O.R.

    1986-03-01

    Evening primrose oil (PO) contains 9% gamma-linolenic acid (GLA) and 75% linoleic acid (LA) each of which are prostaglandin precursors. Corn oil (CO) contains 60% linoleic acid. Fifty day old virgin female rats were given DMBA (5 mg, intragastric). Three weeks post DMBA the rats were separated into two dietary groups of 20% PO and 20% CO, respectively. At 16 weeks post DMBA the rats were killed and mammary tumors analyzed by RIA for PGE/sub 1/, PGE/sub 2/, and 6-keto F/sub 1..cap alpha... PGE/sub 1/ levels in PO fed animals were increased two fold over those fed CO indicating that it is possible to shunt GLA toward monoenoic eicosanoid synthesis. However PGE/sub 2/ and 6 keto F/sub 1..cap alpha../ levels were 5x higher in PO compared to CO. Although this could be attributed to higher cis linoleic acid content of PO, more subtle mechanisms may be responsible.

  11. A review of the incidence and coincidence of uterine and mammary tumors in Wistar and Sprague-Dawley rats based on the RITA database and the role of prolactin.

    Science.gov (United States)

    Harleman, Johannes H; Hargreaves, Adam; Andersson, Håkan; Kirk, Sarah

    2012-08-01

    Wistar rats are frequently selected for use in carcinogenicity studies because of their advantageous survival rate, which is more favorable than other strains such as the Sprague-Dawley (SD) strain. Uterine and mammary tumors are relatively common spontaneous neoplasms of both strains. We examined the incidence and coincidence of uterine tumors and mammary tumors in control animals of both strains within the RITA database. There was a strong inverse relationship between these tumor types in Wistar rats (p 10%.

  12. Adenovirus type 9 E4 open reading frame 1 encodes a transforming protein required for the production of mammary tumors in rats.

    OpenAIRE

    Javier, R T

    1994-01-01

    The E4 region of human adenovirus type 9 (Ad9) transforms established rat embryo fibroblasts and encodes an essential determinant for the production of estrogen-dependent mammary tumors in rats. Testing of the seven Ad9 E4 open reading frames (ORFs) individually for transformation of the established rat embryo fibroblast cell line CREF indicated that only Ad9 E4 ORF1 possessed a significant ability to generate transformed foci on these cells. In contrast, the E4 ORF1 sequences from human Ad5 ...

  13. Analysis of genes involved in the PI3K/Akt pathway in radiation- and MNU-induced rat mammary carcinomas.

    Science.gov (United States)

    Showler, Kaye; Nishimura, Mayumi; Daino, Kazuhiro; Imaoka, Tatsuhiko; Nishimura, Yukiko; Morioka, Takamitsu; Blyth, Benjamin J; Kokubo, Toshiaki; Takabatake, Masaru; Fukuda, Maki; Moriyama, Hitomi; Kakinuma, Shizuko; Fukushi, Masahiro; Shimada, Yoshiya

    2017-03-01

    The PI3K/AKT pathway is one of the most important signaling networks in human breast cancer, and since it was potentially implicated in our preliminary investigations of radiation-induced rat mammary carcinomas, our aim here was to verify its role. We included mammary carcinomas induced by the chemical carcinogen 1-methyl-1-nitrosourea to determine whether any changes were radiation-specific. Most carcinomas from both groups showed activation of the PI3K/AKT pathway, but phosphorylation of AKT1 was often heterogeneous and only present in a minority of carcinoma cells. The negative pathway regulator Inpp4b was significantly downregulated in both groups, compared with in normal mammary tissue, and radiation-induced carcinomas also showed a significant decrease in Pten expression, while the chemically induced carcinomas showed a decrease in Pik3r1 and Pdk1. Significant upregulation of the positive regulators Erbb2 and Pik3ca was observed only in chemically induced carcinomas. However, no genes showed clear correlations with AKT phosphorylation levels, except in individual carcinomas. Only rare carcinomas showed mutations in PI3K/AKT pathway genes, yet these carcinomas did not exhibit stronger AKT phosphorylation. Thus, while AKT phosphorylation is a common feature of rat mammary carcinomas induced by radiation or a canonical chemical carcinogen, the mutation of key genes in the pathways or permanent changes to gene expression of particular signaling proteins do not explain the pathway activation in the advanced cancers. Although AKT signaling likely facilitates cancer development and growth in rat mammary carcinomas, it is unlikely that permanent disruption of the PI3K/AKT pathway genes is a major causal event in radiation carcinogenesis. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  14. Alterations in c-Src/HER1 and estrogen receptor α signaling pathways in mammary gland and tumors of hexachlorobenzene-treated rats

    International Nuclear Information System (INIS)

    Peña, Delfina; Pontillo, Carolina; García, María Alejandra; Cocca, Claudia; Alvarez, Laura; Chiappini, Florencia; Bourguignon, Nadia; Frahm, Isabel; Bergoc, Rosa; Kleiman de Pisarev, Diana; Randi, Andrea

    2012-01-01

    Hexachlorobenzene (HCB) is an organochlorine pesticide that acts as an endocrine disruptor in humans and rodents. The development of breast cancer strongly depends on endocrine conditions modulated by environmental factors. We have demonstrated that HCB is a tumor co-carcinogen in rats and an inducer of proliferation in MCF-7 cells, in an estrogen receptor α (ERα)-dependent manner, and of migration in MDA-MB-231 breast cancer cell line. In the present study, we examined HCB effect on c-Src/human epidermal growth factor receptor (HER1) and ERα signaling pathways in mammary glands and in N-nitroso-N-methylurea (NMU)-induced mammary tumors in rats. Furthermore, we evaluated histopathological changes and serum hormone levels. Rats were separated into four groups: control, HCB (100 mg/kg b.w.), NMU (50 mg/kg b.w.) and NMU-HCB. Our data show that HCB increases c-Src and HER1 activation, c-Src/HER1 association, and Y699-STAT5b and ERK1/2 phosphorylation in mammary glands. HCB also enhances Y537-ERα phosphorylation and ERα/c-Src physical interaction. In tumors, HCB also induces c-Src and HER1 activation, c-Src/HER1 association, as well as T308-Akt and Y699-STAT5b phosphorylation. In addition, the pesticide increases ERα protein content and decreases p-Y537-ERα levels and ERα/c-Src association in tumors. HCB increases serum 17-beta estradiol and prolactin contents and decreases progesterone, FSH and LH levels in rats without tumors, while the opposite effect was observed in rats with tumors. Taken together, our results indicate that HCB induces an estrogenic effect in mammary gland, increasing c-Src/HER1 and ERα signaling pathways. HCB stimulates c-Src/HER1 pathway, but decreases ERα activity in tumors, appearing to shift them towards a higher malignancy phenotype.

  15. Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed comfrey (Symphytum officinale).

    Science.gov (United States)

    Mei, Nan; Guo, Lei; Zhang, Lu; Shi, Leming; Sun, Yongming Andrew; Fung, Chris; Moland, Carrie L; Dial, Stacey L; Fuscoe, James C; Chen, Tao

    2006-09-06

    Comfrey is consumed by humans as a vegetable and a tea, and has been used as an herbal medicine for more than 2000 years. Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. Our previous study suggested that comfrey induces liver tumors by a genotoxic mechanism and that the pyrrolizidine alkaloids in the plant are responsible for mutation induction and tumor initiation in rat liver. In this study, we identified comfrey-induced gene expression profile in the livers of rats. Groups of 6 male transgenic Big Blue rats were fed a basal diet and a diet containing 8% comfrey roots, a dose that resulted in liver tumors in a previous carcinogenicity bioassay. The animals were treated for 12 weeks and sacrificed one day after the final treatment. We used a rat microarray containing 26,857 genes to perform genome-wide gene expression studies. Dietary comfrey resulted in marked changes in liver gene expression, as well as in significant decreases in the body weight and increases in liver mutant frequency. When a two-fold cutoff value and a P-value less than 0.01 were selected, 2,726 genes were identified as differentially expressed in comfrey-fed rats compared to control animals. Among these genes, there were 1,617 genes associated by Ingenuity Pathway Analysis with particular functions, and the differentially expressed genes in comfrey-fed rat livers were involved in metabolism, injury of endothelial cells, and liver injury and abnormalities, including liver fibrosis and cancer development. The gene expression profile provides us a better understanding of underlying mechanisms for comfrey-induced hepatic toxicity. Integration of gene expression changes with known pathological changes can be used to formulate a mechanistic scheme for comfrey-induced liver toxicity and tumorigenesis.

  16. 17a-Ethynyl-5a-androstane-3a, 17 β-diol Treatment of MNU-Induced Mammary Cancer in Rats

    International Nuclear Information System (INIS)

    Ahlem, C.N.; Frincke, J.M.; White, S.K.; Reading, Ch.L.; Trauger, R.J.; Lakshmanaswamy, R.

    2011-01-01

    N-methyl-N-nitrosourea (MNU) induces estrogen-dependent mammary tumors in female Lewis rats. We explored the antineoplastic activity of a synthetic androstane derivative, 17 a-ethynyl-5a-androstane-3a, 17β-diol (HE3235), as a single agent or in combination with docetaxel compared to tamoxifen, anastrazole, and docetaxel mono therapies against MNU-induced mammary tumors in female Lewis rats. Treatment with HE3235 alone rapidly reduced tumor burden, similar in effect to tamoxifen and anastrozole. The combination of HE3235 with docetaxel was more effective than any single agent, although without apparent toxicity. Only HE3235 or HE3235 plus docetaxel continued to suppress tumor growth after cessation of treatment. HE3235 treatment increased immunohistochemical markers of apoptosis and expression of pro apoptotic genes and estrogen receptor beta and decreased expression of anti apoptotic genes, androgen receptor, and estrogen receptor alpha. These data warrant clinical investigation of HE3235 for breast cancer treatment.

  17. Promoting Effects of Milk on the Development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced Mammary Tumors in Rats

    International Nuclear Information System (INIS)

    Ma, De-Fu; Katoh, Ryohei; Zhou, Hong; Wang, Pei-Yu

    2007-01-01

    To assess the effect of milk on the development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors, 48 female Sprague-Dawley rats treated with DMBA were divided into 3 groups and given 1 of 3 test solutions for 20 weeks as their drinking liquid: milk, estrone sulfate solution or tap water. The milk group showed a significantly great incidence (75%) in tumor development compared with the water group (38%) and was comparable to the estrone sulfate group (69%). Mean tumor number per rat in the milk group was significantly higher than that in the water group (p=0.009). We classified the mammary tumors into three histological types: intraductal papilloma, fibroadenoma, and adenocarcinoma. Although the percent of intraductal papilloma and fibroadenoma was almost same among the three groups, malignant tumor was found only in the milk and estrone sulfate groups. In conclusion, our results indicate that milk as well as estrone sulfate promotes the development of DMBA-induced mammary tumors in rat and could be associated with the occurrence of adenocarcinoma

  18. Insulin receptors in the mammary gland

    International Nuclear Information System (INIS)

    Smith, D.H.

    1986-01-01

    Insulin binding studies were conducted using mammary membrane preparations to further the authors understanding of insulin's role in regulating mammary metabolism, particularly ruminant mammary metabolism. Specific objectives were to: (1) characterize insulin binding to bovine mammary microsomes and determine if the specificity and kinetics of binding indicate the presence of insulin receptors in bovine mammary gland; (2) examine and compare insulin binding by liver and mammary microsomes of the pig and dairy cow; (3) examine insulin binding to bovine milk fat globule membranes (MFGM) and evaluate this model's usefulness in assessing insulin receptor regulation in the mammary gland of the cow; (4) examine the effect of dietary fat in insulin binding by rat mammary and liver microsomes. The specificity and kinetics of 125 I-insulin binding of bovine mammary microsomes indicated the presence of insulin receptors in bovine mammary gland. Bovine liver and mammary microsomes specifically bound less 125 I-insulin than did the corresponding porcine microsomes, and mammary microsomes, regardless of species, specifically bound less 125 I-insulin than did liver microsomes. These differences in binding suggest differences in insulin responsiveness between pigs and cattle, as well as between the liver and mammary glands

  19. Effect of dietary supplementation on the prognostic value of urinary and serum 8-isoprostaglandin F2α in chemically-induced mammary carcinogenesis in the rat

    Directory of Open Access Journals (Sweden)

    Białek Sławomir

    2011-03-01

    Full Text Available Abstract Backround The aim of the present study was to assess the effects of zinc or copper and polyphenolic compounds on the 8-isoprostaglandin F2α concentration in the serum and urine of rats with mammary cancer (adenocarcinoma induced with 7,12-dimethylbenz[a]antracene. The research focused on the kinetics of alterations in urinary 8-isoPGF2α at the early stage of carcinogenesis as well as the influence of dietary factors on the process. The impact of selected compounds on the intensity of DMBA - induced carcinogenesis was also assessed. Result and conclusions Administration of DMBA, a compound that inducers mammary tumors in experimental animals, increased the serum and urinary 8-isoPGF2α levels in study rats. In the rat model, diet supplementation with zinc, combined with selected polyphenolic compounds (resveratrol or genistein yielded a statistically significant decrease in the rat serum and urinary biomarker concentration with a simultaneously significant stimulation of carcinogenesis. The results indicate that there is an inverse correlation between the intensity of DMBA-induced carcinogenicity and the level of 8-isoPGF2α in urine and serum of rats.

  20. Abnormal peripubertal development of the rat mammary gland following exposure in utero and during lactation to a mixture of genistein and the food contaminant vinclozolin.

    Science.gov (United States)

    El Sheikh Saad, H; Meduri, G; Phrakonkham, P; Bergès, R; Vacher, S; Djallali, M; Auger, J; Canivenc-Lavier, M C; Perrot-Applanat, M

    2011-07-01

    The impact of early exposure to endocrine disruptor mixtures on mammary gland development is poorly known. Here, we identify the effects of a conception to weaning exposure of rats to the phytoestrogen genistein (G) and/or the antiandrogen vinclozolin (V) at 1mg/kg-d, alone or in association. Using several approaches, we found that G- and GV-exposed rats displayed significantly greater epithelial branching and proliferation, wider terminal end buds than controls at PND35, as well as ductal hyperplasia and periductal fibrosis. Focal branching defects were present in V-exposed rats. An increased ER and AR expression was observed in G- and GV- as compared to V-exposed rats at PND35. Surprisingly, a significant number of GV- and to a lesser extent, V-exposed animals displayed abnormal hyperplasic alveolar structures at PND50. Thus, gestational and lactational exposure to low doses of genistein plus vinclozolin may seriously affect peripubertal development of the rat mammary gland. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. A high protein moderate carbohydrate diet fed at discrete meals reduces early progression of N-methyl-N-nitrosourea-induced breast tumorigenesis in rats

    Directory of Open Access Journals (Sweden)

    Singletary Keith W

    2010-01-01

    Full Text Available Abstract Breast cancer is the most prevalent cancer in American women. Dietary factors are thought to have a strong influence on breast cancer incidence. This study utilized a meal-feeding protocol with female Sprague-Dawley rats to evaluate effects of two ratios of carbohydrate:protein on promotion and early progression of breast tissue carcinomas. Mammary tumors were induced by N-methyl-N-nitrosourea (MNU at 52 d of age. Post-induction, animals were assigned to consume either a low protein high carbohydrate diet (LPHC; 15% and 60% of energy, respectively or a high protein moderate carbohydrate diet (HPMC; 35% and 40% of energy, respectively for 10 wk. Animals were fed 3 meals/day to mimic human absorption and metabolism patterns. The rate of palpable tumor incidence was reduced in HPMC relative to LPHC (12.9 ± 1.4%/wk vs. 18.2 ± 1.3%/wk. At 3 wk, post-prandial serum insulin was larger in the LPHC relative to HPMC (+136.4 ± 33.1 pmol/L vs. +38.1 ± 23.4 pmol/L, while at 10 wk there was a trend for post-prandial IGF-I to be increased in HPMC (P = 0.055. There were no differences in tumor latency, tumor surface area, or cumulative tumor mass between diet groups. The present study provides evidence that reducing the dietary carbohydrate:protein ratio attenuates the development of mammary tumors. These findings are consistent with reduced post-prandial insulin release potentially diminishing the proliferative environment required for breast cancer tumors to progress.

  2. Effect of a Short-Term and Long-Term Melatonin Administration on Mammary Carcinogenesis in Female Sprague-Dawley Rats Influenced by Repeated Psychoemotional Stress

    Directory of Open Access Journals (Sweden)

    M. Kassayová

    2007-01-01

    Full Text Available The aim of this study was to evaluate the effect of melatonin (MEL on N-methyl-N-nitrosourea (NMU-induced mammary carcinogenesis in female Sprague-Dawley rats exposed to repeated psychoemotional stress - immobilization in boxes. NMU was applied intraperitoneally in two doses each of 50 mg/kg b.w. between 40 - 50 postnatal days. Melatonin was administered in drinking water at a concentration of 4 μg/ml daily from 15:00 h to 8:00 h. The application was initiated 5 days prior to the fi rst NMU dose and lasted 15 days, i.e. during the promotion phase of tumour development, or long-term until the end of the experiment (week 20. Immobilization (2 h per day began on the third day after the second carcinogen application and lasted for 7 consecutive days. Short-term MEL administration to immobilized animals increased incidence by 22%, decreased tumour frequency per animal by 26% and reduced tumour volume gain (by 21% when compared to the immobilized group without MEL application. Decreased frequency per animal by 28% and more than a 40% decrease in tumour volume gain and cumulative volume were the most pronounced changes in the animals drinking MEL until the end of the experiment. Long-term MEL administration reduced the number and size of mammary tumours more markedly than its short-term administration. Melatonin decreased certain attributes of mammary carcinogenesis in female rats influenced by psychoemotional stress.

  3. Effects of liarozole fumarate (R85246) in combination with tamoxifen on N-methyl-N-nitrosourea (MNU)-induced mammary carcinoma and uterus in the rat model

    International Nuclear Information System (INIS)

    Goss, Paul E; Strasser-Weippl, Kathrin; Qi, Shangle; Hu, Haiqing

    2007-01-01

    Liarozole fumarate (liarozole – R85246) is a novel compound with characteristics of both aromatase inhibitor (AI) and a retinoic acid metabolism blocking agent (RAMBA). Our objective was to determine the effects of liarozole alone or in combination with tamoxifen on the N-methyl-N-nitrosourea (MNU)-induced rat mammary carcinoma model, as well as on the uterus in ovariectomized immature rats. (1) Tumor burden experiments: Animals bearing one or more tumors greater than 10 mm in diameter were treated for 56 consecutive days with 20 mg/kg or 80 mg/kg of liarozole by oral gavage, tamoxifen 100 μg/kg by subcutaneous injection, or a combination of liarozole and tamoxifen. At the end of the treatment period, total cumulative tumor volume as well as retinoic acid levels were measured. (2) Uterotrophic assay and proliferation experiments: 21-day-old ovariectomized (OVX) Sprague-Dawley rats were treated with 20 mg/kg or 80 mg/kg of liarozole by oral gavage, tamoxifen 1 mg/kg by subcutaneous injection, and combination of both for 4 consecutive days. At the end of the treatment period, uterine weight, epithelial lining cell height and indices of proliferation cell nuclear antigen (PCNA) were measured. The tumor burden experiments in rats bearing estrogen receptor (ER) positive mammary tumours showed that liarozole has a marked anti-tumour effect. In combination with tamoxifen, liarozole had neither an additive nor an antagonistic effect. However, liarozole markedly reduced the uterotrophic effects induced by tamoxifen. Liarozole's antitumor effects on ER positive mammary tumors and its protective effect on the uterus merit further studies to confirm its clinical value in combination with tamoxifen in ER positive postmenopausal breast cancer. Liarozole and other retinomimetics might also be suitable chemoprevention drugs in combination with tamoxifen because of their favorable toxicity profile

  4. The effect of different radiation exposure combined with prolactin on the carcinogenesis of rat mammary tumors

    International Nuclear Information System (INIS)

    Yokoro Kenjiro

    1984-01-01

    Female W/Fu rats were exposed to various doses of respective radiation and some of these irradiated rats further received a continuous supply of prolactin by means of grafting a prolactin producing pituitary tumor as a promoter to make easier the detection of carcinogenic effect of radiation. The results show that, the carcinogenic effect of 2.0 MeV fission neutrons is surprisingly higher than those of others; being about 30, 14 and 4.5 times as high as X-rays, 14.1 MeV fast neutrons and 0.025 eV thermal neutrons respectively. The irradiation field of fission radiation is equivalent to the atomic bomb that exploded in Hiroshima in 1945, so these experimental findings may have some relevance to the recent study on the reassessment of radiation dose of both neutrons and gamma-rays produced by atomic bomb in Hiroshima and Nagasaki

  5. Correlation of regional disease and in vivo PO2 in rat mammary adenocarcinoma.

    OpenAIRE

    Cole, M. A.; Crawford, D. W.; Warner, N. E.; Puffer, H. W.

    1983-01-01

    A knowledge of the distribution of oxygen tension (PO2) and vascularization in neoplasia has been fundamental to understanding relationships between tumor growth, hypoxia, and therapy. We have combined recessed oxygen microcathode and freeze-substitution techniques to correlate in situ PO2 profiles and morphologic features in 7,12-dimethylbenz(a)anthracene (DMBA) tumors in rats. Overlying connective tissue of transplanted tumor was exposed by a 1-2 mm incision and a cross-stitch pattern demar...

  6. Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber).

    Science.gov (United States)

    Liang, Sitai; Mele, James; Wu, Yuehong; Buffenstein, Rochelle; Hornsby, Peter J

    2010-08-01

    The naked mole-rat (NMR, Heterocephalus glaber) is a long-lived mammal in which spontaneous cancer has not been observed. To investigate possible mechanisms for cancer resistance in this species, we studied the properties of skin fibroblasts from the NMR following transduction with oncogenes that cause cells of other mammalian species to form malignant tumors. Naked mole-rat fibroblasts were transduced with a retrovirus encoding SV40 large T antigen and oncogenic Ras(G12V). Following transplantation of transduced cells into immunodeficient mice, cells rapidly entered crisis, as evidenced by the presence of anaphase bridges, giant cells with enlarged nuclei, multinucleated cells, and cells with large number of chromosomes or abnormal chromatin material. In contrast, similarly transduced mouse and rat fibroblasts formed tumors that grew rapidly without crisis. Crisis was also observed after > 40 population doublings in SV40 TAg/Ras-expressing NMR cells in culture. Crisis in culture was prevented by additional infection of the cells with a retrovirus encoding hTERT (telomerase reverse transcriptase). SV40 TAg/Ras/hTERT-expressing NMR cells formed tumors that grew rapidly in immunodeficient mice without evidence of crisis. Crisis could also be induced in SV40 TAg/Ras-expressing NMR cells by loss of anchorage, but after hTERT transduction, cells were able to proliferate normally following loss of anchorage. Thus, rapid crisis is a response of oncogene-expressing NMR cells to growth in an in vivo environment, which requires anchorage independence, and hTERT permits cells to avoid crisis and to achieve malignant tumor growth. The unique reaction of NMR cells to oncogene expression may form part of the cancer resistance of this species.

  7. Correlation of regional disease and in vivo PO2 in rat mammary adenocarcinoma.

    Science.gov (United States)

    Cole, M A; Crawford, D W; Warner, N E; Puffer, H W

    1983-07-01

    A knowledge of the distribution of oxygen tension (PO2) and vascularization in neoplasia has been fundamental to understanding relationships between tumor growth, hypoxia, and therapy. We have combined recessed oxygen microcathode and freeze-substitution techniques to correlate in situ PO2 profiles and morphologic features in 7,12-dimethylbenz(a)anthracene (DMBA) tumors in rats. Overlying connective tissue of transplanted tumor was exposed by a 1-2 mm incision and a cross-stitch pattern demarcated electrode puncture sites for histologic reference. Three buffered salt solutions (BSS) with different PO2 were each allowed to flow through a well over the tumor where electrodes were placed for calibration. Zero electrode oxygen current was recorded from a buffered yeast-agar mixture of zero torr. PO2 was recorded at 5-mu intervals to approximately 1-2 mm. Atmospheric contamination was eliminated by continuous well flow of BSS, 30 torr. Finally, the tumor and surrounding tissues were quick-frozen in vivo with Freon 22 and liquid nitrogen. The tissue block was freeze-substituted and sectioned. PO2 profiles were superimposed onto correspondingly scaled photomicrographs. A viable periphery with a PO2 range of 50-82 torr and a transition to necrotic areas of PO2, 2-13 torr were observed. This transition was characterized by PO2 gradients within distances of 50-300 mu at variable puncture depths. This technique should be useful in further studies of growth, necrosis, and therapy.

  8. Interstitial laser immunotherapy for treatment of metastatic mammary tumors in rats

    Science.gov (United States)

    Figueroa, Daniel; Joshi, Chet; Wolf, Roman F.; Walla, Jonny; Goddard, Jessica; Martin, Mallory; Kosanke, Stanley D.; Broach, Fred S.; Pontius, Sean; Brown, Destiny; Li, Xiaosong; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Chen, Wei R.

    2011-03-01

    Thermal therapy has been used for cancer treatment for more than a century. While thermal effect can be direct, immediate, and controllable, it is not sufficient to completely eradicate tumors, particularly when tumors have metastasized locally or to the distant sites. Metastases are the major cause of treatment failure and cancer deaths. Current available therapies, such as surgery, radiation, and chemotherapy, only have limited curative effects in patients with late-stage, metastatic cancers. Immunotherapy has been considered as the ultimate approach for cancer treatment since a systemic, anti-tumor, immunological response can be induced. Using the combination of photothermal therapy and immunotherapy, laser immunotherapy (LIT),a novel immunotherapy modality for late-stage cancer treatment, has been developed. LIT has shown great promise in pre-clinical studies and clinical breast cancer and melanoma pilot trials. However, the skin color and the depth of the tumor have been challenges for effective treatment with LIT. To induce a thermal destruction zone of appropriate size without causing thermal damage on the skin, we have developed interstitial laser immunotherapy (ILIT) using a cylindrical diffuser. To determine the effectiveness of ILIT, we treated the DMBA-4 metastatic tumors in rats. The thermal damage in tumor tissue was studied using TTC immersion and hematoxolin and eosin (H & E) staining. Also observed was the overall survival of the treated animals. Our results demonstrated that the ILIT could impact a much larger tumor area, and it significantly reduced the surface damage compared with the early version of non-invasive LIT. The survival data also indicate that ILIT has the potential to become an effective tool for the treatment of deeper, larger, and metastatic tumors, with reduced side effects.

  9. Luminal progenitors restrict their lineage potential during mammary gland development.

    Science.gov (United States)

    Rodilla, Veronica; Dasti, Alessandro; Huyghe, Mathilde; Lafkas, Daniel; Laurent, Cécile; Reyal, Fabien; Fre, Silvia

    2015-02-01

    The hierarchical relationships between stem cells and progenitors that guide mammary gland morphogenesis are still poorly defined. While multipotent basal stem cells have been found within the myoepithelial compartment, the in vivo lineage potential of luminal progenitors is unclear. Here we used the expression of the Notch1 receptor, previously implicated in mammary gland development and tumorigenesis, to elucidate the hierarchical organization of mammary stem/progenitor cells by lineage tracing. We found that Notch1 expression identifies multipotent stem cells in the embryonic mammary bud, which progressively restrict their lineage potential during mammary ductal morphogenesis to exclusively generate an ERαneg luminal lineage postnatally. Importantly, our results show that Notch1-labelled cells represent the alveolar progenitors that expand during pregnancy and survive multiple successive involutions. This study reveals that postnatal luminal epithelial cells derive from distinct self-sustained lineages that may represent the cells of origin of different breast cancer subtypes.

  10. Mammary Specific Expression of Cre Recombinase Under the Control of an Endogenous MMTV LTR: A Conditional Knock-Out System

    National Research Council Canada - National Science Library

    Czarneski, Jennifer

    2000-01-01

    .... Mice that carried the Mtv-17 Cre fusion vector would then be mated to mice that had the p53 locus flanked by loxP sites, resulting in the tissue-specific loss of p53 in the mammary gland only. The prediction is that these animals would only develop mammary and not other tumors. We believed that the cre-transgenic mice would also prove useful for other investigators in the mammary gland development and tumorigenesis field.

  11. Diets high in corn oil or extra-virgin olive oil differentially modify the gene expression profile of the mammary gland and influence experimental breast cancer susceptibility.

    Science.gov (United States)

    Moral, Raquel; Escrich, Raquel; Solanas, Montserrat; Vela, Elena; Ruiz de Villa, M Carme; Escrich, Eduard

    2016-06-01

    Nutritional factors, especially dietary lipids, may have a role in the etiology of breast cancer. We aimed to analyze the effects of high-fat diets on the susceptibility of the mammary gland to experimental malignant transformation. Female Sprague-Dawley rats were fed a low-fat, high-corn-oil, or high-extra-virgin olive oil (EVOO) diet from weaning or from induction. Animals were induced with 7,12-dimethylbenz[a]anthracene at 53 days and euthanized at 36, 51, 100 and 246 days. Gene expression profiles of mammary glands were determined by microarrays. Further molecular analyses were performed by real-time PCR, TUNEL and immunohistochemistry. Carcinogenesis parameters were determined at 105 and 246 days. High-corn-oil diet increased body weight and mass when administered from weaning. The EVOO diet did not modify these parameters and increased the hepatic expression of UCP2, suggesting a decrease in intake/expenditure balance. Both diets differentially modified the gene expression profile of the mammary gland, especially after short dietary intervention. Corn oil down-regulated the expression of genes related to immune system and apoptosis, whereas EVOO modified the expression of metabolism genes. Further analysis suggested an increase in proliferation and lower apoptosis in the mammary glands by effect of the high-corn-oil diet, which may be one of the mechanisms of its clear stimulating effect on carcinogenesis. The high-corn-oil diet strongly stimulates mammary tumorigenesis in association with modifications in the expression profile and an increased proliferation/apoptosis balance of the mammary gland.

  12. Molecular cloning and sequence analysis of complementary DNA encoding rat mammary gland medium-chain S-acyl fatty acid synthetase thio ester hydrolase

    International Nuclear Information System (INIS)

    Safford, R.; de Silva, J.; Lucas, C.

    1987-01-01

    Poly(A) + RNA from pregnant rat mammary glands was size-fractionated by sucrose gradient centrifugation, and fractions enriched in medium-chain S-acyl fatty acid synthetase thio ester hydrolase (MCH) were identified by in vitro translation and immunoprecipitation. A cDNA library was constructed, in pBR322, from enriched poly(A) + RNA and screened with two oligonucleotide probes deduced from rat MCH amino acid sequence data. Cross-hybridizing clones were isolated and found to contain cDNA inserts ranging from ∼ 1100 to 1550 base pairs (bp). A 1550-bp cDNA insert, from clone 43H09, was confirmed to encode MCH by hybrid-select translation/immunoprecipitation studies and by comparison of the amino acid sequence deduced from the DNA sequence of the clone to the amino acid sequence of the MCH peptides. Northern blot analysis revealed the size of the MCH mRNA to be 1500 nucleotides, and it is therefore concluded that the 1550-bp insert (including G x C tails) of clone 43H09 represents a full- or near-full-length copy of the MCH gene. The rat MCH sequence is the first reported sequence of a thioesterase from a mammalian source, but comparison of the deduced amino acid sequences of MCH and the recently published mallard duck medium-chain S-acyl fatty acid synthetase thioesterase reveals significant homology. In particular, a seven amino acid sequence containing the proposed active serine of the duck thioesterase is found to be perfectly conserved in rat MCH

  13. The Possible Effect Of Tamoxifen Vs Whole Body Irradiation Treatment On Thyroid Hormones in Female Rats Bearing Mammary Tumors Chemically Induced

    International Nuclear Information System (INIS)

    Abdelgawad, M.R.

    2012-01-01

    Breast cancer is the most common malignancy among women in most developed and developing regions of the world. In women, this drug has tissuespecific effects, acting as an estrogen antagonist on the breast, and as an estrogen agonist on bone, lipid metabolism (increasing high-density lipoprotein cholesterol and decreasing low-density lipoprotein cholesterol), and the endometrium. Thyroid hormones act on almost all organs throughout the body and regulate the basal metabolism of the organism. Thyroid hormone can also stimulate the proliferation in vitro of certain tumor cell lines. The aim of the present study is to evaluate the significant value of tamoxifen and/or irradiation treatment on thyroid hormones in breast cancer bearing female rats. Forty two female Sprague-Dawely rats randomly divided into seven groups and the effect of tamoxifen and post-irradiation was studied on breast cancer chemically induced. The results shows a T 4 and estradiol levels not T 3 were altered in different experimental groups. It could be concluded that irradiation-induced changes in the composition of the mammary microenvironment promote the expression of neoplastic potential by affecting both estradiol and thyroid hormones, and tamoxifen may alter the thyroid hormones. Irradiation and tamoxifen administration may have worth effects on T 4 and estradiol levels and it is recommended to further studies towards the bystander effect of radiation and tamoxifen on the tissue culture and molecular biology scale.

  14. Immune response to a mammary adenocarcinoma. V. Sera from tumor-bearing rats contain multiple factors blocking cell-mediated cytotoxicity.

    Science.gov (United States)

    Huber, S A; Lucas, Z J

    1978-12-01

    Sera from Fischer rats 3 to 13 days after i.p. injection of syngeneic 13762A mammary adenocarcinoma contain three factors specifically blocking cell-mediated cytotoxicity (CMC). The major blocking factor is a 160,000-dalton IgG that combines specifically to cytolytic lymphocytes but not to tumor cells or tumor antigen, and that is not dissociated after treatment with 8 M urea. The other factors have been putatively identified as tumor antigen (less than 70,000 daltons) and as soluble antigen-antibody complexes (greater than 200,000 daltons). Injecting the tumor antigen into tumor-free rats induced spleen cells specifically cytotoxic to the 13762A tumor and provided partial protection to challenge with live tumor cells. Treating soluble antigen-antibody complexes with 8 M urea decreased the size of the blocking activity from greater than 200,000 to less than 70,000 daltons. Although the IgG fraction dissociated from the complex did not block CMC, it did recombine with the tumor antigen fraction to transfer activity to the greater than 200,000-dalton fraction. In contrast, mixing tumor antigen with the IgG fraction that did block CMC did not alter the size of the blocking activities.

  15. Lipidomic fatty acid profile and global gene expression pattern in mammary gland of rats that were exposed to lard-based high fat diet during fetal and lactation periods associated to breast cancer risk in adulthood.

    Science.gov (United States)

    Andrade, Fábia de Oliveira; de Assis, Sonia; Jin, Lu; Fontelles, Camile Castilho; Barbisan, Luís Fernando; Purgatto, Eduardo; Hilakivi-Clarke, Leena; Ong, Thomas Prates

    2015-09-05

    The persistent effects of animal fat consumption during pregnancy and nursing on the programming of breast cancer risk among female offspring were studied here. We have previously found that female offspring of rat dams that consumed a lard-based high-fat (HF) diet (60% fat-derived energy) during pregnancy, or during pregnancy and lactation, were at a reduced risk of developing mammary cancer. To better understand the unexpected protective effects of early life lard exposure, we have applied lipidomics and nutrigenomics approaches to investigate the fatty acid profile and global gene expression patterns in the mammary tissue of the female offspring. Consumption of this HF diet during gestation had few effects on the mammary tissue fatty acids profile of young adult offspring, while exposure from gestation throughout nursing promoted significant alterations in the fatty acids profile. Major differences were related to decreases in saturated fatty acids (SFA) and increases in omega-6 polyunsaturated fatty acids (PUFAs), monounsaturated fatty acids (MUFAs) and conjugated linolenic acid (CLA) concentrations. In addition several differences in gene expression patterns by microarray analysis between the control and in utero or in utero and during lactation HF exposed offspring were identified. Differential dependency network (DDN) analysis indicated that many of the genes exhibited unique connections to other genes only in the HF offspring. These unique connections included Hrh1-Ythdf1 and Repin1-Elavl2 in the in utero HF offspring, and Rnf213-Htr3b and Klf5-Chrna4 in the in utero and lactation HF offspring, compared with the control offspring. We conclude that an exposure to a lard-based HF diet during early life changes the fatty acid profile and transcriptional network in mammary gland in young adult rats, and these changes appear to be consistent with reduced mammary cancer risk observed in our previous study. Copyright © 2015 Elsevier Ireland Ltd. All rights

  16. Ambient oxygen promotes tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Ho Joong Sung

    2011-05-01

    Full Text Available Oxygen serves as an essential factor for oxidative stress, and it has been shown to be a mutagen in bacteria. While it is well established that ambient oxygen can also cause genomic instability in cultured mammalian cells, its effect on de novo tumorigenesis at the organismal level is unclear. Herein, by decreasing ambient oxygen exposure, we report a ∼50% increase in the median tumor-free survival time of p53-/- mice. In the thymus, reducing oxygen exposure decreased the levels of oxidative DNA damage and RAG recombinase, both of which are known to promote lymphomagenesis in p53-/- mice. Oxygen is further shown to be associated with genomic instability in two additional cancer models involving the APC tumor suppressor gene and chemical carcinogenesis. Together, these observations represent the first report directly testing the effect of ambient oxygen on de novo tumorigenesis and provide important physiologic evidence demonstrating its critical role in increasing genomic instability in vivo.

  17. Genes Altered by Intracisternal A Particles in Mouse Mammary Tumorigenesis

    National Research Council Canada - National Science Library

    Crowley, Michael

    1999-01-01

    ...) and murine viral leukemia elements (MuLVs). Expression of MuLVs has lead to the appearance of novel restriction fragments associated with the ecotropic MuLV in D2 HANs and several D2 tumors from BALB/c mice...

  18. Genes Altered by Intracisternal A Particles in Mouse Mammary Tumorigenesis

    National Research Council Canada - National Science Library

    Crowley, Michael

    1997-01-01

    ...) in BALB/c mice which express high levels of intracistemal A-particles (IAP). Differential hybpridization and differential display strategies are being used to isolate transcripts which contained IAP LTR sequences...

  19. Signaling mechanisms in progestin-induced canine mammary tumorigenesis

    NARCIS (Netherlands)

    Gracanin, A.

    2015-01-01

    Breast cancer is the most prominent cancer in women of the Western world with over 1.7 million women newly diagnosed and >500,000 deaths annually. The majority of breast cancers are hormone receptor positive and potentially bear sensitivity towards endocrine treatment. Despite initially effective,

  20. Dose response study of conjugated fatty acid derived from safflower oil on mammary and colon carcinogenesis pretreated with 7,12-dimethylbenz[a]anthracene (DMBA) and 1,2-dimethylhydrazine (DMH) in female Sprague-Dawley rats.

    Science.gov (United States)

    Cheng, Jing Lei; Futakuchi, Mitsuru; Ogawa, Kumiko; Iwata, Toshio; Kasai, Masaaki; Tokudome, Shinkan; Hirose, Masao; Shirai, Tomoyuki

    2003-07-10

    To clarify the chemopreventive effects of conjugated fatty acid derived from safflower oil (CFA-S), rich in conjugated linoleic acid (CLA), on mammary and colon carcinogenesis, 6 week old female Sprague-Dawley (SD) rats received diet containing 0.01, 0.05, 0.1, 1, or 2% CFA-S subsequent to five times subcutaneous injections of 1,2-dimethyl-hydrazine (DMH) at a dose of 40 mg/kg b.w. and a single 50 mg/kg b.w. intragastric application of 7,12-dimethylbenz[a]anthracene (DMBA) during the first 11 days. The experiment was terminated at week 36. Numbers of mammary tumors, colon aberrant crypt foci (ACF), and proliferative indices of mammary tumors, and colon epithelium were analyzed. The 1% dose was found to be optimal for suppression of carcinogenesis in both target organs, a good correlation being noted with between data for cell proliferation. These results suggest that a diet containing appropriate levels of CFA-S may be useful for prevention of mammary and colon cancer.

  1. Induction of experimental mammary carcinogenesis in rats with 7,12-dimethylbenz(aanthracene Indução da carcinogênese mamária experimental em ratas com 7,12-dimetilbenz(aantraceno

    Directory of Open Access Journals (Sweden)

    Alfredo Carlos S. D. Barros

    2004-01-01

    Full Text Available PURPOSE: To test an experimental model of chemical mammary carcinogenesis induction in rats. METHODS: Twenty young virgin Sprague-Dawley female rats, aged 47 days, received 20 mg of 7,12-dimethylbenz(aanthracene (DMBA intragastrically by gavage. Afterwards, at 8 and 13 weeks, their mammary glands were examined. At the end of the experiment, the animals were sacrificed, and the mammary tumors were measured and weighed. Tumor fragments were analyzed using light microscopy. RESULTS: Eight weeks after DMBA injection, 16 rats presented at least 1 breast tumor (80%. After 13 weeks, all of them (100% developed breast carcinomas that were confirmed by histopathological analysis. CONCLUSION: This experimental animal model of chemical mammary induced carcinogenesis is feasible and can be used in further experiments on the role of tumorigenic biomodulator substances.OBJETIVO: Testar um modelo experimental de indução química de carcinogênese mamária em ratas. MATERIAL E MÉTODOS: Com 47 dias de vida, 20 ratas Sprague-Dawley, jovens e virgens, receberam por gavagem intragástrica 20 mg de 7,12-dimetilbenz(aantraceno (DMBA. Oito e 13 semanas depois da injeção de droga as mamas das ratas foram examinadas. Ao final os animais foram sacrificados e fragmentos dos tumores foram estudados ao microscópio. RESULTADO: Oito semanas depois da injeção de DMBA 16 ratas apresentavam tumor nas mamas (80%. Com 13 semanas todas desenvolveram carcinomas de mama (100%, que foram confirmados por análise histopatológica. CONCLUSÃO: Este modelo experimental de indução química de carcinogênese mamária é factível e pode ser empregado em futuras pesquisas para avaliar o papel de substâncias biomoduladoras da tumorigênese.

  2. Dietary administration of δ- and γ-tocopherol inhibits tumorigenesis in the animal model of estrogen-receptor positive, but not HER-2 breast cancer

    Science.gov (United States)

    Smolarek, Amanda K.; So, Jae Young; Burgess, Brenda; Kong, Ah-Ng Tony; Reuhl, Kenneth; Lin, Yong; Shih, Weichung Joe; Li, Guangxun; Lee, Mao-Jung; Chen, Yu-Kuo; Yang, Chung S.; Suh, Nanjoo

    2012-01-01

    Tocopherol, a member of the vitamin E family, consists of four forms designated as α, β, γ, and δ. Several large cancer prevention studies with α-tocopherol have reported no beneficial results, but recent laboratory studies have suggested that δ- and γ-tocopherol may be more effective. In two different animal models of breast cancer, the chemopreventive activities of individual tocopherols were assessed using diets containing 0.3% of tocopherol (α-, δ- or γ-) or 0.3% of a γ-tocopherol rich mixture (γ-TmT). While administration of tocopherols did not prevent human epidermal growth factor receptor 2 (HER2/neu)-driven tumorigenesis, δ- and γ-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague Dawley rats. NMU-treated rats showed an average tumor burden of 10.6 ± 0.8 g in the control group at 11 weeks, whereas dietary administration of δ- and γ-tocopherols significantly decreased tumor burden to 7.2 ± 0.8 g (ptocopherol treatment groups by 42% (ptocopherol did not decrease tumor burden or multiplicity. In mammary tumors, the protein levels of pro-apoptotic markers (BAX, cleaved-caspase 9, cleaved-caspase 3, cleaved-PARP) were increased, while anti-apoptotic markers (Bcl2, XIAP) were inhibited by δ-tocopherol, γ-tocopherol and γ-TmT. Furthermore, markers of cell proliferation (PCNA, PKC α), survival (PPARγ, PTEN, phospho-Akt) and cell cycle (p53, p21) were affected by δ- and γ-tocopherols. Both δ- and γ-tocopherols, but not α-tocopherol, appear to be promising agents for the prevention of hormone-dependent breast cancer. PMID:22964476

  3. Dietary administration of δ- and γ-tocopherol inhibits tumorigenesis in the animal model of estrogen receptor-positive, but not HER-2 breast cancer.

    Science.gov (United States)

    Smolarek, Amanda K; So, Jae Young; Burgess, Brenda; Kong, Ah-Ng Tony; Reuhl, Kenneth; Lin, Yong; Shih, Weichung Joe; Li, Guangxun; Lee, Mao-Jung; Chen, Yu-Kuo; Yang, Chung S; Suh, Nanjoo

    2012-11-01

    Tocopherol, a member of the vitamin E family, consists of four forms designated as α, β, γ, and δ. Several large cancer prevention studies with α-tocopherol have reported no beneficial results, but recent laboratory studies have suggested that δ- and γ-tocopherol may be more effective. In two different animal models of breast cancer, the chemopreventive activities of individual tocopherols were assessed using diets containing 0.3% of tocopherol (α-, δ-, or γ-) or 0.3% of a γ-tocopherol rich mixture (γ-TmT). Although administration of tocopherols did not prevent human epidermal growth factor receptor 2 (HER2/neu)-driven tumorigenesis, δ- and γ-tocopherols inhibited hormone-dependent mammary tumorigenesis in N-methyl-N-nitrosourea (NMU)-treated female Sprague-Dawley rats. NMU-treated rats showed an average tumor burden of 10.6 ± 0.8 g in the control group at 11 weeks, whereas dietary administration of δ- and γ-tocopherols significantly decreased tumor burden to 7.2 ± 0.8 g (P tocopherol treatment groups by 42% (P tocopherol did not decrease tumor burden or multiplicity. In mammary tumors, the protein levels of proapoptotic markers (BAX, cleaved caspase-9, cleaved caspase-3, cleaved PARP) were increased, whereas antiapoptotic markers (Bcl-2, XIAP) were inhibited by δ-tocopherol, γ-tocopherol, and γ-TmT. Furthermore, markers of cell proliferation (PCNA, PKCα), survival (PPAR-γ, PTEN, phospho-Akt), and cell cycle (p53, p21) were affected by δ- and γ-tocopherols. Both δ- and γ-tocopherols, but not α-tocopherol, seem to be promising agents for the prevention of hormone-dependent breast cancer.

  4. The interplay between autophagy and ROS in tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kongara, Sameera [Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ (United States); The Cancer Institute of New Jersey, New Brunswick, NJ (United States); Karantza, Vassiliki, E-mail: karantva@umdnj.edu [Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ (United States); The Cancer Institute of New Jersey, New Brunswick, NJ (United States); Division of Medical Oncology, Department of Internal Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ (United States)

    2012-11-21

    Reactive oxygen species (ROS) at physiological levels are important cell signaling molecules. However, aberrantly high ROS are intimately associated with disease and commonly observed in cancer. Mitochondria are primary sources of intracellular ROS, and their maintenance is essential to cellular health. Autophagy, an evolutionarily conserved process whereby cytoplasmic components are delivered to lysosomes for degradation, is responsible for mitochondrial turnover and removal of damaged mitochondria. Impaired autophagy is implicated in many pathological conditions, including neurological disorders, inflammatory bowel disease, diabetes, aging, and cancer. The first reports connecting autophagy to cancer showed that allelic loss of the essential autophagy gene BECLIN1 (BECN1) is prevalent in human breast, ovarian, and prostate cancers and that Becn1{sup +/-} mice develop mammary gland hyperplasias, lymphomas, lung and liver tumors. Subsequent studies demonstrated that Atg5{sup -/-} and Atg7{sup -/-} livers give rise to adenomas, Atg4C{sup -/-} mice are susceptible to chemical carcinogenesis, and Bif1{sup -/-} mice are prone to spontaneous tumors, indicating that autophagy defects promote tumorigenesis. Due to defective mitophagy, autophagy-deficient cells accumulate damaged mitochondria and deregulated ROS levels, which likely contribute to their tumor-initiating capacity. However, the role of autophagy in tumorigenesis is complex, as more recent work also revealed tumor dependence on autophagy: autophagy-competent mutant-Ras-expressing cells form tumors more efficiently than their autophagy-deficient counterparts; similarly, FIP200 deficiency suppresses PyMT-driven mammary tumorigenesis. These latter findings are attributed to the fact that tumors driven by powerful oncogenes have high metabolic demands catered to by autophagy. In this review, we discuss the relationship between ROS and autophagy and summarize our current knowledge on their functional interactions

  5. The interplay between autophagy and ROS in tumorigenesis

    International Nuclear Information System (INIS)

    Kongara, Sameera; Karantza, Vassiliki

    2012-01-01

    Reactive oxygen species (ROS) at physiological levels are important cell signaling molecules. However, aberrantly high ROS are intimately associated with disease and commonly observed in cancer. Mitochondria are primary sources of intracellular ROS, and their maintenance is essential to cellular health. Autophagy, an evolutionarily conserved process whereby cytoplasmic components are delivered to lysosomes for degradation, is responsible for mitochondrial turnover and removal of damaged mitochondria. Impaired autophagy is implicated in many pathological conditions, including neurological disorders, inflammatory bowel disease, diabetes, aging, and cancer. The first reports connecting autophagy to cancer showed that allelic loss of the essential autophagy gene BECLIN1 (BECN1) is prevalent in human breast, ovarian, and prostate cancers and that Becn1 +/- mice develop mammary gland hyperplasias, lymphomas, lung and liver tumors. Subsequent studies demonstrated that Atg5 -/- and Atg7 -/- livers give rise to adenomas, Atg4C -/- mice are susceptible to chemical carcinogenesis, and Bif1 -/- mice are prone to spontaneous tumors, indicating that autophagy defects promote tumorigenesis. Due to defective mitophagy, autophagy-deficient cells accumulate damaged mitochondria and deregulated ROS levels, which likely contribute to their tumor-initiating capacity. However, the role of autophagy in tumorigenesis is complex, as more recent work also revealed tumor dependence on autophagy: autophagy-competent mutant-Ras-expressing cells form tumors more efficiently than their autophagy-deficient counterparts; similarly, FIP200 deficiency suppresses PyMT-driven mammary tumorigenesis. These latter findings are attributed to the fact that tumors driven by powerful oncogenes have high metabolic demands catered to by autophagy. In this review, we discuss the relationship between ROS and autophagy and summarize our current knowledge on their functional interactions in tumorigenesis.

  6. Ethanol-induced oxidative stress and acetaldehyde formation in rat mammary tissue: Potential factors involved in alcohol drinking promotion of breast cancer

    International Nuclear Information System (INIS)

    Castro, Gerardo D.; Rodriguez de Castro, Carmen; Maciel, Maria E.; Fanelli, Silvia L.; Cignoli de Ferreyra, Elida; Gomez, Maria I. Diaz; Castro, Jose A.

    2006-01-01

    Recent studies from our laboratory provided evidence that part of the carcinogenic effects of ethanol consumption might be related to its in situ metabolism at cytosolic and microsomal levels, to the mutagen acetaldehyde and to hydroxyl and 1-hydroxyethyl radicals. In this work, we report on our experiments where Sprague-Dawley female rats were exposed to the standard Lieber and De Carli diet for 28 days. We observed: the induction of the (xanthineoxidoreductase mediated) cytosolic and microsomal (lipoxygenase mediated) pathways of ethanol metabolism; promotion of oxidative stress as shown by increased formation of lipid hydroperoxides; delay in the t-butylhydroperoxide induced chemiluminiscence, and a significant decrease in protein sulfhydryls. In addition, the epithelial cells showed ultrastructural alterations consisting of markedly irregular nuclei, with frequent invaginations at the level of the nuclear envelope, condensation of chromatin around the inner nuclear membrane, and marked dilatation of the nuclear pores showing filamentous material exiting to the cytoplasm. In conclusion, the presence in mammary epithelial cells of cytosolic and microsomal pathways of ethanol bioactivation to carcinogenic and to tumorigenic metabolites might play a role in alcohol promotion of breast cancer

  7. Mammary carcinoma diagnostics and therapy

    International Nuclear Information System (INIS)

    Fischer, Uwe; Baum, Friedemann

    2014-01-01

    The book on mammary carcinoma diagnostics and therapy covers the following issues: development, anatomy and physiology of the mammary glands, pathology of benign and malign mammary gland changes, non-imaging diagnostics; mammography; ultrasonic mammography; magnetic resonance tomography of the mammary glands; imaging diagnostics findings; mammary interventions; examination concepts; operative therapy of the mammary carcinoma; chemotherapy of the mammary carcinoma; radio-oncological therapy of the mammary carcinoma; logistics in a medical center for mammary gland diseases; logistics in an interdisciplinary center for mammary diseases; dialogue conduction and psycho-social attendance.

  8. Downregulation of ATM Gene and Protein Expression in Canine Mammary Tumors.

    Science.gov (United States)

    Raposo-Ferreira, T M M; Bueno, R C; Terra, E M; Avante, M L; Tinucci-Costa, M; Carvalho, M; Cassali, G D; Linde, S D; Rogatto, S R; Laufer-Amorim, R

    2016-11-01

    The ataxia telangiectasia mutated (ATM) gene encodes a protein associated with DNA damage repair and maintenance of genomic integrity. In women, ATM transcript and protein downregulation have been reported in sporadic breast carcinomas, and the absence of ATM protein expression has been associated with poor prognosis. The aim of this study was to evaluate ATM gene and protein expression in canine mammary tumors and their association with clinical outcome. ATM gene and protein expression was evaluated by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, respectively, in normal mammary gland samples (n = 10), benign mammary tumors (n = 11), nonmetastatic mammary carcinomas (n = 19), and metastatic mammary carcinomas (n = 11). Lower ATM transcript levels were detected in benign mammary tumors and carcinomas compared with normal mammary glands (P = .011). Similarly, lower ATM protein expression was observed in benign tumors (P = .0003), nonmetastatic mammary carcinomas (P ATM gene or protein levels were detected among benign tumors and nonmetastatic and metastatic mammary carcinomas (P > .05). The levels of ATM gene or protein expression were not significantly associated with clinical and pathological features or with survival. Similar to human breast cancer, the data in this study suggest that ATM gene and protein downregulation is involved in canine mammary gland tumorigenesis. © The Author(s) 2016.

  9. Enhanced antitumor activity of surface-modified iron oxide nanoparticles and an α-tocopherol derivative in a rat model of mammary gland carcinosarcoma.

    Science.gov (United States)

    Horák, Daniel; Pustovyy, Vitaliy Igorovych; Babinskyi, Andrii Valeriyovich; Palyvoda, Olga Mikhailovna; Chekhun, Vasyl Fedorovich; Todor, Igor Nikolaevich; Kuzmenko, Oleksandr Ivanovich

    2017-01-01

    Maghemite (γ-Fe 2 O 3 ) nanoparticles were obtained by coprecipitation of ferrous and ferric salts in an alkaline medium followed by oxidation; the nanoparticles were coated with poly( N,N -dimethylacrylamide) (PDMA) and characterized by transmission electron microscopy, attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering, thermogravimetric and elemental analyses, and magnetic measurements in terms of particle morphology, size, polydispersity, amount of coating, and magnetization, respectively. The effects of α-tocopherol (Toc) and its phenolic (Toc-6-OH) and acetate (Toc-6-Ac) derivatives on Fe 2+ release from γ-Fe 2 O 3 @PDMA, as well as from γ-Fe 2 O 3 and CuFe 2 O 4 nanoparticles (controls), were examined in vitro using 1,10-phenanthroline. The presence of tocopherols enhanced spontaneous Fe 2+ release from nanoparticles, with Toc-6-OH exhibiting more activity than neat Toc. All of the nanoparticles tested were found to initiate blood lipid oxidation in a concentration-dependent manner, as determined by analysis of 2-thiobarbituric acid reactive species. Wistar rats with Walker-256 carcinosarcoma (a model of mammary gland carcinosarcoma) received Toc-6-Ac, magnetic nanoparticles, or their combination per os, and the antitumor activity of each treatment was determined in vivo. γ-Fe 2 O 3 @PDMA nanoparticles exhibited increased antitumor activity compared to both commercial CuFe 2 O 4 particles and the antitumor drug doxorubicin. Moreover, increased antitumor activity was observed after combined administration of γ-Fe 2 O 3 @PDMA nanoparticles and Toc-6-Ac; however, levels of bilirubin, aspartate aminotransferase, and white bloods normalized and did not differ from those of the intact controls. The antitumor activity of the γ-Fe 2 O 3 nanoparticles strongly correlated with Fe 2+ release from the nanoparticles but not with nanoparticle-initiated lipid peroxidation in vitro.

  10. Dynamics of tumor oxygenation, CD31 staining and transforming growth factor-β levels after treatment with radiation or cyclophosphamide in the rat 13762 mammary carcinoma

    International Nuclear Information System (INIS)

    Kakeji, Yoshihiro; Maehara, Yoshihiko; Ikebe, Masahiko; Teicher, Beverly A.

    1997-01-01

    Purpose: Tumors are dynamic tissues that undergo marked molecular, biochemical, and physiologic changes in response to cytotoxic anticancer therapies. Understanding the changes in tumor oxygenation and transforming growth factor-β expression may allow improved treatment regimens to be developed. Methods and Materials: The effects of a single dose of radiation therapy (20 Gy) or a single dose of chemotherapy (cyclophosphamide, 250 mg/kg) on several molecular and physiologic parameters of the rat 13762 mammary carcinoma growing subcutaneously in female Fischer 344 rats were explored. Results: Treatment of the tumor-bearing animals with 20 Gy of radiation killed about two logs (99%) of the 13762 tumor cells, and treatment with cyclophosphamide (250 mg/kg) killed about 1.5 logs (95%) of the 13762 tumor cells. Hypoxia, as determined by a pO 2 electrode, initially decreased in the tumors of treated animals until 6 h. posttreatment and then increased, so that 24 h. after administration of the radiation therapy or the chemotherapy the number of intratumoral vessels as determined by CD31 staining increased until about 24 h after cytotoxic therapy. Transforming growth factor-β1, measured by radioimmunoassay, peaked in the serum between 6 h and 18 h and again between 72 h and 96 h after radiation therapy and peaked in the tumor at 24 h and again at 72 h after radiation therapy. The first serum peak after cyclophosphamide was 3 h after drug injection, with second peaks at 36 h and 48 h after drug administration. In the tumor, transforming growth factor-β1 peaked between 6 h and 8 h after drug administration and again 36 h and 72 h after drug. Apoptosis was maximal 6 h after 20 Gy and 24 h after cyclophosphamide. Vascular endothelial growth factor was also increased in tumors after cytotoxic therapy. Conclusions: These changes in the tumor physiologic status are sufficient to protect the tumor from a second cytotoxic insult administered days afterwards and to result in a

  11. Insulin-like growth factor (IGF)-I obliterates the pregnancy-associated protection against mammary carcinogenesis in rats: evidence that IGF-I enhances cancer progression through estrogen receptor-α activation via the mitogen-activated protein kinase pathway

    International Nuclear Information System (INIS)

    Thordarson, Gudmundur; Slusher, Nicole; Leong, Harriet; Ochoa, Dafne; Rajkumar, Lakshmanaswamy; Guzman, Raphael; Nandi, Satyabrata; Talamantes, Frank

    2004-01-01

    Pregnancy protects against breast cancer development in humans and rats. Parous rats have persistently reduced circulating levels of growth hormone, which may affect the activity of the growth hormone/insulin-like growth factor (IGF)-I axis. We investigated the effects of IGF-I on parity-associated protection against mammary cancer. Three groups of rats were evaluated in the present study: IGF-I-treated parous rats; parous rats that did not receive IGF-I treatment; and age-matched virgin animals, which also did not receive IGF-I treatment. Approximately 60 days after N-methyl-N-nitrosourea injection, IGF-I treatment was discontinued and all of the animal groups were implanted with a silastic capsule containing 17β-estradiol and progesterone. The 17β-estradiol plus progesterone treatment continued for 135 days, after which the animals were killed. IGF-I treatment of parous rats increased mammary tumor incidence to 83%, as compared with 16% in parous rats treated with 17β-estradiol plus progesterone only. Tumor incidence and average number of tumors per animal did not differ between IGF-I-treated parous rats and age-matched virgin rats. At the time of N-methyl-N-nitrosourea exposure, DNA content was lowest but the α-lactalbumin concentration highest in the mammary glands of untreated parous rats in comparison with age-matched virgin and IGF-I-treated parous rats. The protein levels of estrogen receptor-α in the mammary gland was significantly higher in the age-matched virgin animals than in untreated parous and IGF-I-treated parous rats. Phosphorylation (activation) of the extracellular signal-regulated kinase-1/2 (ERK1/2) and expression of the progesterone receptor were both increased in IGF-I-treated parous rats, as compared with those in untreated parous and age-matched virgin rats. Expressions of cyclin D 1 and transforming growth factor-β 3 in the mammary gland were lower in the age-matched virgin rats than in the untreated parous and IGF-I-treated parous

  12. Transplacental and mammary passage of radioactivity in rats treated vaginally and orally with [14C]propranolol

    International Nuclear Information System (INIS)

    Buttar, H.S.; Moffatt, J.H.; Bura, C.

    1988-01-01

    Single doses (10 mg/kg) of an aqueous solution of [14C]propranolol were administered either orally (po) or intravaginally (ivg) on gestational d 15, or on postpartum d 7-10. Upon ivg administration, [14C]propranolol was quickly transferred to systemic circulation and the mean blood [14C] concentrations were significantly greater during the first 0.25-2 h than in po dosed counterparts. About 98% of the ivg applied dose was absorbed after 6 h in gravid rats, and the combined 6-h excretions of radioactivity in the urine (ivg = 24.6%; po = 22.9%) and feces (ivg = 16.8%; po = 14.6%) were equivalent in both groups. At the end of 6 h, the levels of [14C] in the urinary bladder, adrenal, uterus, ovary, spleen, skeletal muscle, brain, heart, lung and fat were significantly higher in ivg treated rats than po dosed animals. Compared with the maternal plasma (ivg = 0.76; po = 0.88 microgram/ml), the mean concentrations of [14C] in the placentas were similar in both groups, while the amounts of [14C] were three to five times lower in the amniotic fluids and the fetuses of both po and ivg treated dams. In lactating rats, over 99% of the administered radioactivity was absorbed from the vagina within 6 h. The blood concentrations of [14C] were significantly elevated at 0.5 and 1 h in the per vaginam treated animals, and afterward the disappearance rate of [14C] followed a similar course in both groups. Following ivg application, the milk radioactivity peaked at 0.5 h and declined rapidly. However, the appearance of [14C] in milk was rather slow after oral dosing: the milk [14C] peaked between 2 and 3 h posttreatment and remained steady thereafter. The milk to blood (M/B) [14C] concentration ratios were markedly greater during 0.5 to 1 h in the ivg group than in their po dosed counterparts

  13. Luminal epithelial cells within the mammary gland can produce basal cells upon oncogenic stress.

    Science.gov (United States)

    Hein, S M; Haricharan, S; Johnston, A N; Toneff, M J; Reddy, J P; Dong, J; Bu, W; Li, Y

    2016-03-17

    In the normal mammary gland, the basal epithelium is known to be bipotent and can generate either basal or luminal cells, whereas the luminal epithelium has not been demonstrated to contribute to the basal compartment in an intact and normally developed mammary gland. It is not clear whether cellular heterogeneity within a breast tumor results from transformation of bipotent basal cells or from transformation and subsequent basal conversion of the more differentiated luminal cells. Here we used a retroviral vector to express an oncogene specifically in a small number of the mammary luminal epithelial cells and tested their potential to produce basal cells during tumorigenesis. This in-vivo lineage-tracing work demonstrates that luminal cells are capable of producing basal cells on activation of either polyoma middle T antigen or ErbB2 signaling. These findings reveal the plasticity of the luminal compartment during tumorigenesis and provide an explanation for cellular heterogeneity within a cancer.

  14. Control of ductal vs. alveolar differentiation of mammary clonogens and susceptibility to radiation-induced mammary cancer

    International Nuclear Information System (INIS)

    Kamiya, Kenji; Yokoro, Kenjiro; Clifton, K.H.; Gould, M.N.

    1991-01-01

    We have developed an in vitro-in vivo transplantation assay for measuring the concentration of clonogenic epithelial cells in cell suspensions of rat mammary tissue. Rat mammary clonogens from organoid cultures are capable of the same degree of PLDR as clonogens in vivo. The growth and differentiation of mammary clonogens to alveolar colonies or ductal colonies is regulated as follows: a) in the presence of E 2 and high prolactin (Prl), cortisol induces mammary clonogens to proliferate and differentiate to form alveolar colonies which secrete milk and begin losing clonogenic potential, b) in cortisol deficient rats, Prl and E 2 synergistically stimulate non-secretory ductal colonies, formation of which retain clonogenic potential, c) E 2 without progesterone stimulates alveolar colony formation in the presence of cortical and high Prl, d) progesterone inhibits mammary clonogen differentiation to milk-producing cells and induces ductogenesis in a dose responsive fashion in the presence of E 2 , cortisol and high Prl. High prolactin levels coupled with glucocorticoid deficiency increases the susceptibility to mammary carcinogenesis following low dose radiation exposure by increasing the number of total mammary clonogens which are the presumptive target cells and by stimulating their proliferation after exposure. (author)

  15. Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed comfrey (Symphytum officinale)

    OpenAIRE

    Mei Nan; Guo Lei; Zhang Lu; Shi Leming; Sun Yongming; Fung Chris; Moland Carrie L; Dial Stacey L; Fuscoe James C; Chen Tao

    2006-01-01

    Abstract Background Comfrey is consumed by humans as a vegetable and a tea, and has been used as an herbal medicine for more than 2000 years. Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. Our previous study suggested that comfrey induces liver tumors by a genotoxic mechanism and that the pyrrolizidine alkaloids in the plant are responsible for mutation induction and tumor initiation in rat liver. Results In this study, we identified comfrey...

  16. Raman Spectroscopic Analysis Reveals Abnormal Fatty Acid Composition in Tumor Micro- and Macroenvironments in Human Breast and Rat Mammary Cancer.

    Science.gov (United States)

    You, Sixian; Tu, Haohua; Zhao, Youbo; Liu, Yuan; Chaney, Eric J; Marjanovic, Marina; Boppart, Stephen A

    2016-09-06

    Fatty acids play essential roles in the growth and metastasis of cancer cells. To facilitate their avid growth and proliferation, cancer cells not only alter the fatty acid synthesis and metabolism intracellularly and extracellularly, but also in the macroenvironment via direct or indirect pathways. We report here, using Raman micro-spectroscopy, that an increase in the production of polyunsaturated fatty acids (PUFAs) was identified in both cancerous and normal appearing breast tissue obtained from breast cancer patients and tumor-bearing rats. By minimizing confounding effects from mixed chemicals and optimizing the signal-to-noise ratio of Raman spectra, we observed a large-scale transition from monounsaturated fatty acids to PUFAs in the tumor while only a small subset of fatty acids transitioned to PUFAs in the tumor micro- and macroenvironment. These data have important implications for further clarifying the macroenvironmental effect of cancer progression and provide new potential approaches for characterizing the tumor micro- and macroenvironment of breast cancer in both pre-clinical animal studies and clinical applications.

  17. Immunoglobins in mammary secretions

    DEFF Research Database (Denmark)

    Hurley, W L; Theil, Peter Kappel

    2013-01-01

    Immunoglobulins secreted in colostrum and milk by the lactating mammal are major factors providing immune protection to the newborn. Immunoglobulins in mammary secretions represent the cumulative immune response of the lactating animal to exposure to antigenic stimulation that occurs through...... the immunoglobulins found in mammary secretions in the context of their diversity of structure, origin, mechanisms of transfer, and function....

  18. Mammary sensitivity to protein restriction and re-alimentation.

    Science.gov (United States)

    Goodwill, M G; Jessop, N S; Oldham, J D

    1996-09-01

    The present study tested the influence of protein undernutrition and re-alimentation on mammary gland size and secretory cell activity in lactating rats. During gestation, female Sprague-Dawley rats were offered a high-protein diet (215 g crude protein (N x 6.25; CP)/kg DM; H); litters were standardized to twelve pups at parturition. During lactation, two diets were offered ad libitum, diet H and a low-protein diet (90 g CP/kg DM; L). Lactational dietary treatments were the supply ad libitum of either diet H (HHH) or diet L (LLL) for the first 12 d of lactation, or diet L transferring to diet H on either day 6 (LHH) or 9 (LLH) of lactation. On days 1, 6, 9 and 12 of lactation, rats from each group (n > or = 6) were used to estimate mammary dry mass, fat, protein, DNA and RNA; the activities of lactose synthetase (EC 2.4.1.22) enzyme and Na+,K(+)-ATPase (EC 3.6.1.37) were also measured. Rats offered a diet considered protein sufficient (H) from day 1 of lactation showed a decrease in mammary dry mass and fat but an increase in DNA, RNA and protein on day 6, after which there was no further change, except for mammary protein which continued to increase. However, rats offered diet L showed a steady loss in mammary mass and fat throughout the 12 d lactation period and no change in mammary DNA, RNA or protein. Rats previously protein restricted for either the first 6 or 9 d of lactation had their mammary dry mass and mammary fat loss halted and showed a rapid increase in mammary DNA, RNA and protein on re-alimentation. Lactose production in group HHH, as measured by lactose synthetase activity, was similar on days 1 and 6 of lactation, after which a significant increase was seen. Protein-restricted rats showed no change in lactose synthetase activity during the 12 d experimental period. Changing from diet L to diet H led to a significant increase in lactose synthetase activity to levels comparable with those offered diet H from day 1. These results show that rats

  19. Investigating the Role of Cooperative Interactions Between the Neu Protooncogene and the Other erbB Family Members in Rat Mammary Carcinogenesis

    Science.gov (United States)

    1999-07-01

    antiestrogen tamoxifen or the monoterpene perillyl alcohol can prevent the formation of neu associated mammary cancers in this transgenic model. II...general breast cancer prevention agents; the monoterpenes (perillyl alcohol) and determine if the number of preneoplastic lesions and cancers

  20. Linked expression of Ah receptor, ARNT, CYP1A1, and CYP1B1 in rat mammary epithelia, in vitro, is each substantially elevated by specific extracellular matrix interactions that precede branching morphogenesis.

    Science.gov (United States)

    Larsen, Michele Campaigne; Brake, Paul B; Pollenz, Richard S; Jefcoate, Colin R

    2004-11-01

    Cytochrome P4501B1 (CYP1B1), the major constitutively expressed CYP in the rat mammary gland, is induced by Ah-receptor (AhR) ligands, while CYP1A1 is predominantly expressed only after induction. These CYPs contribute to carcinogenic activation of polycyclic aromatic hydrocarbons (PAHs). AhR, ARNT, and CYP1B1 were only weakly expressed, even after 2,3,7,8-tetrachlorodibenzo-p-dioxin induction, when rat mammary epithelial cells (RMEC) were cultured on plastic. RMEC cultured on the extracellular matrix (ECM), Matrigel, or on a floating gel of collagen I demonstrated branching morphogenesis and substantially increased basal CYP1B1 and induced CYP1A1 expression, in parallel with large increases in AhR and ARNT expression. Branching was more pronounced in the Wistar Kyoto than in the Wistar Furth rat strain. Although EGF enhanced branching, neither strain nor growth factor treatment substantially impacted CYP expression. Increased AhR and ARNT expression is observed within 24 h of dispersal on Matrigel, substantially prior to branch formation. Culture on thin layers of collagen I, collagen IV, and laminin, respectively, failed to reproduce the branching morphogenesis or increases in AhR, ARNT, or CYP expression. However, adherent, gelled collagen I recapitulated the increased protein expression, without supporting branching. This increased protein expression was closely paralleled by enhanced expression of beta-catenin and E-cadherin, components of cell-cell adhesion complexes. A synthetic peptide that selectively antagonizes integrin-ECM interactions reduced branch formation, without diminishing AhR, ARNT, and CYP expression. These data demonstrate that early ECM surface adhesion interactions mediate AhR and ARNT expression, which enhances CYP expression, independent of branching morphogenesis.

  1. Effect of Prunella vulgaris L extract on hyperplasia of mammary ...

    African Journals Online (AJOL)

    p < 0.01) in rats treated with highdose PVE. Conclusion: These results suggest that PVE exerts anti-HMG effect in rats induced by estrogen and progestogen. Keywords: Prunella vulgaris L; Anti-inflammatory; Anti-hyperplasia of mammary gland ...

  2. Social isolation induces autophagy in the mouse mammary gland: link to increased mammary cancer risk.

    Science.gov (United States)

    Sumis, Allison; Cook, Katherine L; Andrade, Fabia O; Hu, Rong; Kidney, Emma; Zhang, Xiyuan; Kim, Dominic; Carney, Elissa; Nguyen, Nguyen; Yu, Wei; Bouker, Kerrie B; Cruz, Idalia; Clarke, Robert; Hilakivi-Clarke, Leena

    2016-10-01

    Social isolation is a strong predictor of early all-cause mortality and consistently increases breast cancer risk in both women and animal models. Because social isolation increases body weight, we compared its effects to those caused by a consumption of obesity-inducing diet (OID) in C57BL/6 mice. Social isolation and OID impaired insulin and glucose sensitivity. In socially isolated, OID-fed mice (I-OID), insulin resistance was linked to reduced Pparg expression and increased neuropeptide Y levels, but in group-housed OID fed mice (G-OID), it was linked to increased leptin and reduced adiponectin levels, indicating that the pathways leading to insulin resistance are different. Carcinogen-induced mammary tumorigenesis was significantly higher in I-OID mice than in the other groups, but cancer risk was also increased in socially isolated, control diet-fed mice (I-C) and G-OID mice compared with that in controls. Unfolded protein response (UPR) signaling (GRP78; IRE1) was upregulated in the mammary glands of OID-fed mice, but not in control diet-fed, socially isolated I-C mice. In contrast, expression of BECLIN1, ATG7 and LC3II were increased, and p62 was downregulated by social isolation, indicating increased autophagy. In the mammary glands of socially isolated mice, but not in G-OID mice, mRNA expressions of p53 and the p53-regulated autophagy inducer Dram1 were upregulated, and nuclear p53 staining was strong. Our findings further indicated that autophagy and tumorigenesis were not increased in Atg7(+/-) mice kept in social isolation and fed OID. Thus, social isolation may increase breast cancer risk by inducing autophagy, independent of changes in body weight. © 2016 Society for Endocrinology.

  3. Activation of int-1 and int-2 loci in GRf mammary tumors.

    Science.gov (United States)

    Gray, D A; Jackson, D P; Percy, D H; Morris, V L

    1986-10-30

    The Mtv-2 locus is known to be associated with a high mammary tumor incidence (97%) and early development of mammary tumors (3-13 months) in GR mice. However, it was not previously known whether the provirus which resides at the Mtv-2 locus is tumorigenic in and of itself or whether reintegration of proviruses generated from Mtv-2 is required for tumorigenesis. Foster-nursing GR mice on C57/BL mice eliminates the milk-borne source of GR virus, and allows the study of Mtv-2 derived proviruses alone. Using this approach, we have tested predictions which follow from the "positional" versus "reintegrational" models of tumorigenesis. Specifically, we have examined tumors from primary foster-nursed (GRf) mice to determine if MMTV proviruses derived from Mtv-2 were scattered randomly throughout the genome or were clustered in the vicinity of the int-1 and int-2 loci, which are thought to be associated with mammary tumorigenesis. It was found that the majority of spontaneous GRf mammary tumors that were tested have MMTV proviral integrations in either or both of the int-1 and int-2 loci and have transcription of either or both of the int loci. Tumors induced by Mtv-2, therefore, appear to have arisen via a mechanism similar to the activation of the int loci by exogenous (milk-borne) MMTV proviruses.

  4. Expression and function of the protein tyrosine phosphatase receptor J (PTPRJ in normal mammary epithelial cells and breast tumors.

    Directory of Open Access Journals (Sweden)

    Chanel E Smart

    Full Text Available The protein tyrosine phosphatase receptor J, PTPRJ, is a tumor suppressor gene that has been implicated in a range of cancers, including breast cancer, yet little is known about its role in normal breast physiology or in mammary gland tumorigenesis. In this paper we show that PTPRJ mRNA is expressed in normal breast tissue and reduced in corresponding tumors. Meta-analysis revealed that the gene encoding PTPRJ is frequently lost in breast tumors and that low expression of the transcript associated with poorer overall survival at 20 years. Immunohistochemistry of PTPRJ protein in normal human breast tissue revealed a distinctive apical localisation in the luminal cells of alveoli and ducts. Qualitative analysis of a cohort of invasive ductal carcinomas revealed retention of normal apical PTPRJ localization where tubule formation was maintained but that tumors mostly exhibited diffuse cytoplasmic staining, indicating that dysregulation of localisation associated with loss of tissue architecture in tumorigenesis. The murine ortholog, Ptprj, exhibited a similar localisation in normal mammary gland, and was differentially regulated throughout lactational development, and in an in vitro model of mammary epithelial differentiation. Furthermore, ectopic expression of human PTPRJ in HC11 murine mammary epithelial cells inhibited dome formation. These data indicate that PTPRJ may regulate differentiation of normal mammary epithelia and that dysregulation of protein localisation may be associated with tumorigenesis.

  5. Notch3 marks clonogenic mammary luminal progenitor cells in vivo.

    Science.gov (United States)

    Lafkas, Daniel; Rodilla, Veronica; Huyghe, Mathilde; Mourao, Larissa; Kiaris, Hippokratis; Fre, Silvia

    2013-10-14

    The identity of mammary stem and progenitor cells remains poorly understood, mainly as a result of the lack of robust markers. The Notch signaling pathway has been implicated in mammary gland development as well as in tumorigenesis in this tissue. Elevated expression of the Notch3 receptor has been correlated to the highly aggressive "triple negative" human breast cancer. However, the specific cells expressing this Notch paralogue in the mammary gland remain unknown. Using a conditionally inducible Notch3-CreERT2(SAT) transgenic mouse, we genetically marked Notch3-expressing cells throughout mammary gland development and followed their lineage in vivo. We demonstrate that Notch3 is expressed in a highly clonogenic and transiently quiescent luminal progenitor population that gives rise to a ductal lineage. These cells are capable of surviving multiple successive pregnancies, suggesting a capacity to self-renew. Our results also uncover a role for the Notch3 receptor in restricting the proliferation and consequent clonal expansion of these cells.

  6. Prevention of mammary carcinogenesis by short-term estrogen and progestin treatments

    International Nuclear Information System (INIS)

    Rajkumar, Lakshmanaswamy; Guzman, Raphael C; Yang, Jason; Thordarson, Gudmundur; Talamantes, Frank; Nandi, Satyabrata

    2004-01-01

    Women who have undergone a full-term pregnancy before the age of 20 have one-half the risk of developing breast cancer compared with women who have never gone through a full-term pregnancy. This protective effect is observed universally among women of all ethnic groups. Parity in rats and mice also protects them against chemically induced mammary carcinogenesis. Seven-week-old virgin Lewis rats were given N-methyl-N-nitrosourea. Two weeks later the rats were treated with natural or synthetic estrogens and progestins for 7–21 days by subcutaneous implantation of silastic capsules. In our current experiment, we demonstrate that short-term sustained exposure to natural or synthetic estrogens along with progestins is effective in preventing mammary carcinogenesis in rats. Treatment with 30 mg estriol plus 30 mg progesterone for 3 weeks significantly reduced the incidence of mammary cancer. Short-term exposure to ethynyl estradiol plus megesterol acetate or norethindrone was effective in decreasing the incidence of mammary cancers. Tamoxifen plus progesterone treatment for 3 weeks was able to confer only a transient protection from mammary carcinogenesis, while 2-methoxy estradiol plus progesterone was effective in conferring protection against mammary cancers. The data obtained in the present study demonstrate that, in nulliparous rats, long-term protection against mammary carcinogenesis can be achieved by short-term treatments with natural or synthetic estrogen and progesterone combinations

  7. In Utero Exposure to Cadmium, Mammary Gland Development, and Breast Cancer Risk

    National Research Council Canada - National Science Library

    Webster, Jennifer D

    2007-01-01

    .... Previous studies have shown that in utero exposure to cadmium at the levels present in some human environments accelerated puberty onset and altered some of the indicators of mammary gland development in rats...

  8. Modelling Cooperative Tumorigenesis in Drosophila

    Science.gov (United States)

    2018-01-01

    The development of human metastatic cancer is a multistep process, involving the acquisition of several genetic mutations, tumour heterogeneity, and interactions with the surrounding microenvironment. Due to the complexity of cancer development in mammals, simpler model organisms, such as the vinegar fly, Drosophila melanogaster, are being utilized to provide novel insights into the molecular mechanisms involved. In this review, we highlight recent advances in modelling tumorigenesis using the Drosophila model, focusing on the cooperation of oncogenes or tumour suppressors, and the interaction of mutant cells with the surrounding tissue in epithelial tumour initiation and progression. PMID:29693007

  9. Modelling Cooperative Tumorigenesis in Drosophila

    Directory of Open Access Journals (Sweden)

    Helena E. Richardson

    2018-01-01

    Full Text Available The development of human metastatic cancer is a multistep process, involving the acquisition of several genetic mutations, tumour heterogeneity, and interactions with the surrounding microenvironment. Due to the complexity of cancer development in mammals, simpler model organisms, such as the vinegar fly, Drosophila melanogaster, are being utilized to provide novel insights into the molecular mechanisms involved. In this review, we highlight recent advances in modelling tumorigenesis using the Drosophila model, focusing on the cooperation of oncogenes or tumour suppressors, and the interaction of mutant cells with the surrounding tissue in epithelial tumour initiation and progression.

  10. Biological and genetic properties of the p53 null preneoplastic mammary epithelium

    Science.gov (United States)

    Medina, Daniel; Kittrell, Frances S.; Shepard, Anne; Stephens, L. Clifton; Jiang, Cheng; Lu, Junxuan; Allred, D. Craig; McCarthy, Maureen; Ullrich, Robert L.

    2002-01-01

    The absence of the tumor suppressor gene p53 confers an increased tumorigenic risk for mammary epithelial cells. In this report, we describe the biological and genetic properties of the p53 null preneoplastic mouse mammary epithelium in a p53 wild-type environment. Mammary epithelium from p53 null mice was transplanted serially into the cleared mammary fat pads of p53 wild-type BALB/c female to develop stable outgrowth lines. The outgrowth lines were transplanted for 10 generations. The outgrowths were ductal in morphology and progressed through ductal hyperplasia and ductal carcinoma in situ before invasive cancer. The preneoplastic outgrowth lines were immortal and exhibited activated telomerase activity. They are estrogen and progesterone receptor-positive, and aneuploid, and had various levels of tumorigenic potential. The biological and genetic properties of these lines are distinct from those found in most hyperplastic alveolar outgrowth lines, the form of mammary preneoplasia occurring in most traditional models of murine mammary tumorigenesis. These results indicate that the preneoplastic cell populations found in this genetically engineered model are similar in biological properties to a subset of precurser lesions found in human breast cancer and provide a unique model to identify secondary events critical for tumorigenicity and invasiveness.

  11. Use of mammary epithelial antigens as markers in mammary neoplasia

    International Nuclear Information System (INIS)

    Ceriani, R.L.; Peterson, J.A.; Blank, E.W.

    1979-01-01

    Cell-type specific antigens of the mammary epithelial cells can be used as markers of breast neoplasia. Methods are proposed for the detection of metastatic mammary tissue in vivo by injection of [ 125 I]-labeled antibodies against the mammary epithelial antigens. In addition, the reduced expression of mammary epithelial cell antigens in neoplastic breast cells, quantitated here on a cell per cell basis by flow cytofluorimetry, is a marker of neoplasia and an indication of a deletion accompanying the neoplastic transformation of these cells. (Auth.)

  12. Stromal Adipocyte Enhancer-binding Protein (AEBP1) Promotes Mammary Epithelial Cell Hyperplasia via Proinflammatory and Hedgehog Signaling*

    Science.gov (United States)

    Holloway, Ryan W.; Bogachev, Oleg; Bharadwaj, Alamelu G.; McCluskey, Greg D.; Majdalawieh, Amin F.; Zhang, Lei; Ro, Hyo-Sung

    2012-01-01

    Disruption of mammary stromal-epithelial communication leads to aberrant mammary gland development and induces mammary tumorigenesis. Macrophages have been implicated in carcinogenesis primarily by creating an inflammatory microenvironment, which promotes growth of the adjacent epithelial cells. Adipocyte enhancer-binding protein 1 (AEBP1), a novel proinflammatory mediator, promotes macrophage inflammatory responsiveness by inducing NF-κB activity, which has been implicated in tumor cell growth and survival by aberrant sonic hedgehog (Shh) expression. Here, we show that stromal macrophage AEBP1 overexpression results in precocious alveologenesis in the virgin AEBP1 transgenic (AEBP1TG) mice, and the onset of ductal hyperplasia was accelerated in AEBP1TG mice fed a high fat diet, which induces endogenous AEBP1 expression. Transplantation of AEBP1TG bone marrow cells into non-transgenic (AEBP1NT) mice resulted in alveolar hyperplasia with up-regulation of NF-κB activity and TNFα expression as displayed in the AEBP1TG mammary macrophages and epithelium. Shh expression was induced in AEBP1TG macrophages and RAW264.7 macrophages overexpressing AEBP1. The Shh target genes Gli1 and Bmi1 expression was induced in the AEBP1TG mammary epithelium and HC11 mammary epithelial cells co-cultured with AEBP1TG peritoneal macrophages. The conditioned AEBP1TG macrophage culture media promoted NF-κB activity and survival signal, Akt activation, in HC11 cells, whereas such effects were abolished by TNFα neutralizing antibody treatment. Furthermore, HC11 cells displayed enhanced proliferation in response to AEBP1TG macrophages and their conditioned media. Our findings highlight the role of AEBP1 in the signaling pathways regulating the cross-talk between mammary epithelium and stroma that could predispose the mammary tissue to tumorigenesis. PMID:22995915

  13. Stromal adipocyte enhancer-binding protein (AEBP1) promotes mammary epithelial cell hyperplasia via proinflammatory and hedgehog signaling.

    Science.gov (United States)

    Holloway, Ryan W; Bogachev, Oleg; Bharadwaj, Alamelu G; McCluskey, Greg D; Majdalawieh, Amin F; Zhang, Lei; Ro, Hyo-Sung

    2012-11-09

    Disruption of mammary stromal-epithelial communication leads to aberrant mammary gland development and induces mammary tumorigenesis. Macrophages have been implicated in carcinogenesis primarily by creating an inflammatory microenvironment, which promotes growth of the adjacent epithelial cells. Adipocyte enhancer-binding protein 1 (AEBP1), a novel proinflammatory mediator, promotes macrophage inflammatory responsiveness by inducing NF-κB activity, which has been implicated in tumor cell growth and survival by aberrant sonic hedgehog (Shh) expression. Here, we show that stromal macrophage AEBP1 overexpression results in precocious alveologenesis in the virgin AEBP1 transgenic (AEBP1(TG)) mice, and the onset of ductal hyperplasia was accelerated in AEBP1(TG) mice fed a high fat diet, which induces endogenous AEBP1 expression. Transplantation of AEBP1(TG) bone marrow cells into non-transgenic (AEBP1(NT)) mice resulted in alveolar hyperplasia with up-regulation of NF-κB activity and TNFα expression as displayed in the AEBP1(TG) mammary macrophages and epithelium. Shh expression was induced in AEBP1(TG) macrophages and RAW264.7 macrophages overexpressing AEBP1. The Shh target genes Gli1 and Bmi1 expression was induced in the AEBP1(TG) mammary epithelium and HC11 mammary epithelial cells co-cultured with AEBP1(TG) peritoneal macrophages. The conditioned AEBP1(TG) macrophage culture media promoted NF-κB activity and survival signal, Akt activation, in HC11 cells, whereas such effects were abolished by TNFα neutralizing antibody treatment. Furthermore, HC11 cells displayed enhanced proliferation in response to AEBP1(TG) macrophages and their conditioned media. Our findings highlight the role of AEBP1 in the signaling pathways regulating the cross-talk between mammary epithelium and stroma that could predispose the mammary tissue to tumorigenesis.

  14. Radiogenic neoplasia in thyroid and mammary clonogens

    International Nuclear Information System (INIS)

    Clifton, K.H.

    1993-01-01

    The induction of cancer by ionizing radiation is a matter of great practical importance to the nuclear industry, to national defense, to radiological medicine and to the general public. It is increasingly apparent that carcinogenesis is one of the leading dose-limiting effects of radiation exposure (Co90). Quantitative information at the cellular level is essential to an understanding of the mechanisms of radiogenic neoplastic initiation and the stages of promotion and progression to overt neoplasia. We have developed two experimental models, the rat thyroid and rat mammary clonogen transplant systems, for the quantitative study of radiation carcinogenesis at the cellular level in vivo (C185). The most important steps taken or completed during the current grant year include: (a) demonstration of the high age-dependent radiosensitivity of prepubertal rat mammary clonogens to radiogenic damage which may influence their susceptibility to neoplastic initiation, and (b) demonstration of the feasibility of using a molecular test for clonogenicity in which Simple Sequence Repeats in the DNA serve as identifying signals of the genotypic origin of the cells. We have also (c) set up a large carcinogenesis experiment to test the effect of close intercellular contact in thyroid glands in situ on promotion-progression of radiogenically initiated clonogens, (d) achieved considerable further concentration of thyroid clonogens, and (e) begun to explore whether thyroid cells can be induced to give rise to three dimensional multicellular structures in culture in reconstituted basement membrane. These are discussed in this report

  15. Mammary gland stem cells

    DEFF Research Database (Denmark)

    Fridriksdottir, Agla J R; Petersen, Ole W; Rønnov-Jessen, Lone

    2011-01-01

    Distinct subsets of cells, including cells with stem cell-like properties, have been proposed to exist in normal human breast epithelium and breast carcinomas. The cellular origins of epithelial cells contributing to gland development, tissue homeostasis and cancer are, however, still poorly...... and differences between mouse and human gland development with particular emphasis on the identity and localization of stem cells, and the influence of the surrounding microenvironment. It is concluded that while recent advances in the field have contributed immense insight into how the normal mammary gland...... develops and is maintained, significant discrepancies exist between the mouse and human gland which should be taken into consideration in current and future models of mammary stem cell biology....

  16. Inhibitory effects of a polypeptide thymic factor on the development of 7,12-dimethylbenz(a)anthragene-induced mammary adenocarcinoma in female rats

    Energy Technology Data Exchange (ETDEWEB)

    Anisimov, V.N.; Danetskaya, E.V.; Morozov, V.G.; Khavinson, V.Kh.

    1980-01-01

    It has come to be recognized that tumor growth is accompanied by inhibition of cellular immunity and the function of the T lymphocytes. Restitution of T lymphocyte function by means of several pharmacologic agents such as levamisole, phenformin, or epithalamin (an epiphyseal factor) has, in a number of cases, been accompanied by growth inhibition of both spontaneous and induced tumors. In addition, the importance of the thymus in the regulation of T lymphocytes and in antitumor immunity has been recognized. Several indicators point to the fact that the thymus contains physiologically active substances which stimulate T cell-dependent immunity and prevent the occurrence of neoplasms. These considerations have led to attempts at isolation of active thymic factors and studies on their effects on the appearance and growth of tumors. Previously, a thymic factor - thymarin - had been isolated which imparted immunocompetence to the T lymphocytes. This factor differs from other thymic preparations, including thymosine, in terms of a number of physicochemical characteristics and is a polypeptide with a molecular weight of 5000. This study is concerned with its effects on tumor development - mammary gland adenocarcinoma induced in animals with a chemical carcinogen.

  17. Risk of mammary oncogenesis from exposure to neutrons or gamma rays: experimental methodology and early findings

    International Nuclear Information System (INIS)

    Clifton, K.H.; Sridharan, B.N.; Gould, M.N.

    1976-01-01

    A project has been initiated to define the risk of oncogenesis per rad of high or low linear energy transfer (LET) radiation per surviving mammary cell and its modification by hormones. This work was undertaken because: (a) mammary carcinoma is the principle neoplastic disease of American women; (b) rats have been demonstrated to be remarkably susceptible to mammary oncogenesis following neutron irradiation; (c) rats are similar to women in the importance of hormones to carcinoma induction and progression in their mammary glands; and (d) exposure to neutrons is likely to increase with increasing use of nuclear reactors and development of neutron radiotherapy sources. To measure mammary cell survival and, ultimately, postirradiation repair capacity, the authors are developing an in-vivo end-point dilution assay based on the formation of glandular structures after the transplantation of known numbers of monodispersed rat mammary epithelial cell suspensions. Such grafts initially give rise to alveolus-like spheres and, with time, to complete glands. Growth and secretion can be stimulated in them by hormonal manipulation. In the short-term assays and the longer-term carcinogenesis studies, elevated endogenous mammotropic hormone, prolactin (MtH) levels have been induced by grafting of anterior pituitary tissue or of MtT (MtH-secreting pituitary tumours). Steroid hormone levels have been manipulated by surgical ablation or injection. Irradiations have been performed with a modified neutron fission spectrum generated by a Triga reactor, or with 137 Cs γ rays. Results with two inbred rat strains indicate: (a) that the type (carcinoma or fibroadenoma), incidence and latency of mammary tumours is markedly influenced by the circulating levels of MtH: and (b) that adrenal deficiency markedly enhances the induction of mammary carcinomas in irradiated rats with high endogenous MtH levels. Further studies are in progress. (author)

  18. Anaplastic thyroid cancer, tumorigenesis and therapy.

    LENUS (Irish Health Repository)

    O'Neill, J P

    2010-03-01

    Anaplastic thyroid cancer (ATC) is a fatal endocrine malignancy. Current therapy fails to significantly improve survival. Recent insights into thyroid tumorigenesis, post-malignant dedifferentiation and mode of metastatic activity offer new therapeutic strategies.

  19. Effects of Recurrent Stress and a Music Intervention on Tumor Progression and Indices of Distress in an MNU-induced Mammary Cancer in Rats

    Science.gov (United States)

    2011-03-04

    consumption (Brown & Grunberg, 1995; O’Connor & Eikelboom, 2000; Rickards, Job, & Boakes, 1997; Marti, Marti, & Armario , 1994; Zylan & Brown, 1996...Biobehavioral Reviews, 29, 4-5, 829-841. Marti, O., Marti, J., & Armario , A. (1994). Effects of chronic stress on food intake in rats: Influence of

  20. Quantitative Assessment of Mammary Gland Density in Rodents Using Digital Image Analysis

    Directory of Open Access Journals (Sweden)

    Thompson Henry J

    2011-06-01

    Full Text Available Abstract Background Rodent models have been used extensively to study mammary gland development and for studies of toxicology and carcinogenesis. Mammary gland gross morphology can visualized via the excision of intact mammary gland chains following fixation and staining with carmine using a tissue preparation referred to as a whole mount. Methods are described for the automated collection of digital images from an entire mammary gland whole mount and for the interrogation of digital data using a "masking" technique available with Image-Pro® plus image analysis software (Mediacybernetics. Silver Spring, MD. Results Parallel to mammographic analysis in humans, measurements of rodent mammary gland density were derived from area-based or volume-based algorithms and included: total circumscribed mammary fat pad mass, mammary epithelial mass, and epithelium-free fat pad mass. These values permitted estimation of absolute mass of mammary epithelium as well as breast density. The biological plausibility of these measurements was evaluated in mammary whole mounts from rats and mice. During mammary gland development, absolute epithelial mass increased linearly without significant changes in mammographic density. Treatment of rodents with tamoxifen, 9-cis-retinoic acid, or ovariectomy, and occurrence of diet induced obesity decreased both absolute epithelial mass and mammographic density. The area and volumetric methods gave similar results. Conclusions Digital image analysis can be used for screening agents for potential impact on reproductive toxicity or carcinogenesis as well as for mechanistic studies, particularly for cumulative effects on mammary epithelial mass as well as translational studies of mechanisms that explain the relationship between epithelial mass and cancer risk.

  1. Pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes of rats with mammary gland cancer induced by N-methyl nitrosourea.

    Science.gov (United States)

    Carrera, M P; Ramírez-Expósito, M J; Valenzuela, M T; García, M J; Mayas, M D; Arias de Saavedra, J M; Sánchez, R; Pérez, M C; Martínez-Martos, J M

    2005-02-01

    Pyrrolidon carboxypeptidase is an omega-peptidase that hydrolyses N-terminal pyroglutamyl residues from biologically active peptides such as gonadotropin-releasing and thyrotrophin-releasing hormones. We previously described a decrease in both rat and human pyrrolidon carboxypeptidase activity with breast cancer, suggesting that gonadotropin-releasing hormone may be an important local intracrine, autocrine and/or paracrine hormonal factor in the pathogenesis of breast cancer while playing a role in the tumoral process. However, the other susceptible substrate of pyrrolidon carboxypeptidase, thyrotrophin-releasing hormone, may also be modified with breast cancer, supporting an association between breast cancer and thyroid disorders. The present work analyses soluble and membrane-bound pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes in N-methyl nitrosourea-induced breast cancer in rats. Our aim was to determine the possible relationship between gonadotropin-releasing hormone and thyrotrophin-releasing hormone regulation through pyrrolidon carboxypeptidase activity. We propose that pyrrolidon carboxypeptidase activity dysregulation at various local and systemic levels may participate in the initiation, promotion and progression of breast cancer induced in rat by N-methyl nitrosourea through the increase in gonadotropin-releasing hormone. Since pyrrolidon carboxypeptidase activity also acts on thyrotrophin-releasing hormone, the dysregulation of this enzyme's activity could indirectly affect hypothalamus-pituitary-thyroid axis function, and thus potentially represent a link between the diseases of thyroid and breast cancer.

  2. Cloning and Characterizing Genes Involved in Monoterpene Induced Mammary Tumor Regression.

    Science.gov (United States)

    1996-10-01

    AD GRANT NUMBER DAMDI7-94-J-4041 TITLE: Cloning and Characterizing Genes Involved in Monoterpene Induced Mammary Tumor Regression PRINCIPAL...October 1996 Annual (1 Sep 95 - 31 Aug 96) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Cloning and Characterizing Genes Involved in Monoterpene Induced... Monoterpene -induced/repressed genes were identified in regressing rat mammary carcinomas treated with dietary limonene using a newly developed method

  3. Molecular mechanisms of thyroid tumorigenesis

    International Nuclear Information System (INIS)

    Krause, K.; Fuehrer, D.

    2008-01-01

    Thyroid nodules are the most frequent endocrine disorder and occur in approximately 30% of the German population. Thyroid nodular disease constitutes a very heterogeneous entity. A striking diversity of possible functional and morphological features of a thyroid tumour derived from the same thyroid ancestor cell, is a hallmark of thyroid tumorigenesis and is due to specific genetic alterations. Defects in known candidate genes can be found in up to 70% of differentiated thyroid carcinomas and determine the respective cancer phenotype. Papillary thyroid cancers (PTC) harbour BRAF (or much less frequently RAS) mutations in sporadically occurring tumours, while radiation-induced PTC display chromosomal rearrangements such as RET, TRK, APR9 / BRAF. These genetic events results in constitutive MAPKinase activation. Follicular thyroid cancers (FTC) harbour RAS mutations or PAX8/ PPARγ rearrangements, both of which, however have also been identified in follicular adenoma. In addition, recent studies show, that activation of PI3K/AKT signalling occurs with high frequency in follicular thyroid tumours. Undifferentiated (anaplastic) thyroid cancers (ATC) display genetic features of FTC or PTC, in addition to aberant activation of multiple tyrosinkinase pathways (overexpression or mutations in PI3K and MAPK pathways). This underscores the concept of a sequential evolution of ATC from differentiated thyroid cancer, a process widely conceived to be triggered by p53 inactivation. In contrast, the molecular pathogenesis of benign thyroid tumours, in particular cold thyroid nodules is less known, except for toxic thyroid nodules, which arise from constitutive activation of cAMP signalling, predominantly through TSHR mutations. (orig.)

  4. Mammary tuberculosis: percutaneous treatment of a mammary tuberculous abscess

    International Nuclear Information System (INIS)

    Romero, C.; Carreira, C.; Cereceda, C.; Pinto, J.; Lopez, R.; Bolanos, F.

    2000-01-01

    It is currently very rare to find mammary involvement in cases of tuberculosis, in either primary or secondary form. Diagnosis is classically clinical and microbiological, and the basic techniques used in imaging diagnosis are mammography and ultrasound. Computed tomography may define the involvement of the thoracic wall in those cases which present as mammary masses adhering to deep levels, and is also able to evaluate accompanying pulmonary disease, if it is present. Traditionally, treatment has consisted of quadrantectomy and specific antibiotic therapy. We present a case of tuberculous mammary abscess secondary to pulmonary disease, which was treated by percutaneous drainage controlled by CT and specific antibiotic therapy. We revise the diagnosis, differential diagnosis and treatment of mammary tuberculosis. (orig.)

  5. Mammary tuberculosis: percutaneous treatment of a mammary tuberculous abscess

    Energy Technology Data Exchange (ETDEWEB)

    Romero, C.; Carreira, C.; Cereceda, C.; Pinto, J. [Servicio de Radiologia, Hospital Virgen de la Salud, Toledo (Spain); Lopez, R.; Bolanos, F. [Servicio de Cirugia, Hospital Virgen de la Salud, Toledo (Spain)

    2000-03-01

    It is currently very rare to find mammary involvement in cases of tuberculosis, in either primary or secondary form. Diagnosis is classically clinical and microbiological, and the basic techniques used in imaging diagnosis are mammography and ultrasound. Computed tomography may define the involvement of the thoracic wall in those cases which present as mammary masses adhering to deep levels, and is also able to evaluate accompanying pulmonary disease, if it is present. Traditionally, treatment has consisted of quadrantectomy and specific antibiotic therapy. We present a case of tuberculous mammary abscess secondary to pulmonary disease, which was treated by percutaneous drainage controlled by CT and specific antibiotic therapy. We revise the diagnosis, differential diagnosis and treatment of mammary tuberculosis. (orig.)

  6. Msx-1 and Msx-2 in mammary gland development.

    Science.gov (United States)

    Satoh, Kennichi; Ginsburg, Erika; Vonderhaar, Barbara K

    2004-04-01

    Homeobox genes do not generally function alone to determine cell fate and morphogenesis. Rather it is the distinct combination of various members of the homeobox family of genes and their spatiotemporal patterns of expression that determine cell identity and function. Functional redundancy often makes it difficult to clearly discern the role of any one given homeobox gene. The roles that Msx1 and Msx2 play in branching morphogenesis of the mammary gland are only now becoming more evident. Many signaling pathways and transcription factors are implicated in how these homeobox genes correctly determine the morphological development of the gland. Overexpression of Msx1 and Msx2 may also be involved in tumorigenesis. Additional studies are needed to elucidate the roles of these genes in both breast development and cancer.

  7. Studies with 17 beta(16 alpha-[125I]iodo)-estradiol, an estrogen receptor-binding radiopharmaceutical, in rats bearing mammary tumors

    International Nuclear Information System (INIS)

    Gatley, S.J.; Shaughnessy, W.J.; Inhorn, L.; Leiberman, L.M.

    1981-01-01

    We have studied the distribution of 17 beta(16 alpha-[125I]iodo)-estradiol (I-E2) in tumor-bearing and normal rats. High early adrenal-to-blood ratios (up to 22 at 5 min) were seen in all groups, but this fell to six at 1 hr. Uterus-to-blood ratios of 15 were found, and these were fairly constant up to 2 hr after administration. Uptake of label in the uterus, but not in the adrenals, was sensitive to excess diethylstilbestrol, which competes with I-E2 for estrogen receptors. Mean tumor-to-blood ratios of 1.4, 5.5, and 8.7 were seen at 1 hr in rats with transplanted, spontaneous, and N-nitrosomethylurea-induced tumors, respectively. Diethylstilbestrol was shown to reduce uptake of label by spontaneous tumors. Most of the radioactivity was excreted in the bile by 1 hr. Better estrogen-receptor-binding radiopharmaceuticals can probably be designed

  8. Keratinocyte Growth Factor Causes Cystic Dilation of the Mammary Glands of Mice: Interactions of Keratinocyte Growth Factor, Estrogen, and Progesterone In Vivo

    OpenAIRE

    Yi, Eunhee S.; Bedoya, Adriana A.; Lee, Hyesun; Kim, Seokhyun; Housley, Regina M.; Aukerman, Sharon L.; Tarpley, John E.; Starnes, Charles; Yin, Songmei; Pierce, Glenn F.; Ulich, Thomas R.

    1994-01-01

    Keratinocyte growth factor (KGF) is a paracrine mediator of epithelial cell proliferation that has been reported to induce marked proliferation of mammary epithelium in rats. In this study, systemic administration of KGF into naive and oophorectomized mice causes mammary gland proliferation, as evidenced histologically by the appearance of cysts lined by a single layer of epithelium and by hyperplastic epithelium. Whole mount preparations of the mammary glands reveal that the histologically n...

  9. 16α-[77Br]bromoestradiol-17β: a high specific-activity, gamma-emitting tracer with uptake in rat uterus and induced mammary tumors

    International Nuclear Information System (INIS)

    Katzenellenbogen, J.A.; Senderoff, S.G.; McElvany, K.D.; O'Brien, H.A. Jr.; Welch, M.J.

    1981-01-01

    16α-[ 77 Br]bromoestradiol-17β (compound 1) has been synthesized by radiobromination of estrone enoldiacetate. Tissue uptake studies performed 1 hr after administration of compound 1 to immature or mature female rats showed uterus-to-blood ratios of 13, with nontarget tissue-to-blood ratios ranging from 0.6 to 2. Co-administration of unlabeled estradiol caused a selective depression in the uterine uptake with no effect on nontarget tissue uptake. In adult animals bearing adenocarcinomas induced by DMBA (7,12-dimethylbenz(a)anthracene), tumor-to-blood ratios of 6.3 were obtained, this uptake also being depressed in animals treated with unlabeled estradiol. The studies demonstrate that compound 1 has suitable binding properties and sufficiently high specific activity so that its uptake in estrogen target tissues in vivo is mediated primarily by the estrogen receptor. Furthermore, they suggest that this compound may be suitable for imaging human breast tumors that contain estrogen receptors

  10. 16 alpha-[77Br]bromoestradiol-17 beta: a high specific-activity, gamma-emitting tracer with uptake in rat uterus and uterus and induced mammary tumors

    International Nuclear Information System (INIS)

    Katzenellenbogen, J.A.; Senderoff, S.G.; McElvany, K.D.; O'Brien, H.A. Jr.; Welch, M.J.

    1981-01-01

    16 alpha-[77Br]bromoestradiol-17 beta (Compound 1) has been synthesized by radiobromination of estrone enoldiacetate. Tissue uptake studies performed 1 h after administration of Compound 1 to immature or mature female rats showed uterus-to-blood ratios of 13, with nontarget issue-to-blood ratios ranging from 0.6 to 2. Co-administration of unlabelled estradiol caused a selective depression in the uterine uptake with no effect on nontarget tissue uptake. In adult animals bearing adenocarcinomas induced by DMBA (7,12-dimethylbenz(a)anthracene), tumor-to-blood ratios of 6.3 were obtained, this uptake also being depressed in animals treated with unlabeled estradiol. The studies demonstrate that Compound 1 has suitable binding properties and sufficiently high specific activity so that its uptake in estrogen target tissues in vivo is mediated primarily by the estrogen receptor. Furthermore, they suggest that this compound may be suitable for imaging human breast tumors that contain estrogen receptors

  11. Aging is associated with an expansion of CD49fhi mammary stem cells that show a decline in function and increased transformation potential.

    Science.gov (United States)

    Dong, Qiaoxiang; Gao, Hui; Shi, Yuanshuo; Zhang, Fuchuang; Gu, Xiang; Wu, Anqi; Wang, Danhan; Chen, Yuanhong; Bandyopadhyay, Abhik; Yeh, I-Tien; Daniel, Benjamin J; Chen, Yidong; Zou, Yi; Rebel, Vivienne L; Walter, Christi A; Lu, Jianxin; Huang, Changjiang; Sun, Lu-Zhe

    2016-11-15

    Breast cancer incidence increases during aging, yet the mechanism of age-associated mammary tumorigenesis is unclear. Mammary stem cells are believed to play an important role in breast tumorigenesis, but how their function changes with age is unknown. We compared mammary epithelial cells isolated from young and old mammary glands of different cohorts of C57BL6/J and BALB/c mice, and our findings revealed that old mammary glands were characterized by increased basal cell pool comprised of mostly CD49f hi cells, altered luminal-to-basal cell ratio, and irregular ductal morphology. More interestingly, basal stem cells in old mice were increased in frequency, but showed a functional decline of differentiation and increased neoplastic transformation potential. Gene signature enrichment analysis revealed a significant enrichment of a luminal cell gene expression signature in the basal stem cell-enriched population from old mice, suggesting some luminal cells were expressing basal markers. Immunofluorescence staining confirmed the presence of luminal cells with high CD49f expression in hyperplastic lesions implicating these cells as undergoing luminal to basal phenotypic changes during aging. Whole transcriptome analysis showed elevated immune and inflammatory responses in old basal stem cells and stromal cells, which may be the underlying cause for increased CD49f hi basal-like cells in aged glands.

  12. Ligand-independent canonical Wnt activity in canine mammary tumor cell lines associated with aberrant LEF1 expression.

    Directory of Open Access Journals (Sweden)

    Ana Gracanin

    Full Text Available Pet dogs very frequently develop spontaneous mammary tumors and have been suggested as a good model organism for breast cancer research. In order to obtain an insight into underlying signaling mechanisms during canine mammary tumorigenesis, in this study we assessed the incidence and the mechanism of canonical Wnt activation in a panel of 12 canine mammary tumor cell lines. We show that a subset of canine mammary cell lines exhibit a moderate canonical Wnt activity that is dependent on Wnt ligands, similar to what has been described in human breast cancer cell lines. In addition, three of the tested canine mammary cell lines have a high canonical Wnt activity that is not responsive to inhibitors of Wnt ligand secretion. Tumor cell lines with highly active canonical Wnt signaling often carry mutations in key members of the Wnt signaling cascade. These cell lines, however, carry no mutations in the coding regions of intracellular Wnt pathway components (APC, β-catenin, GSK3β, CK1α and Axin1 and have a functional β-catenin destruction complex. Interestingly, however, the cell lines with high canonical Wnt activity specifically overexpress LEF1 mRNA and the knock-down of LEF1 significantly inhibits TCF-reporter activity. In addition, LEF1 is overexpressed in a subset of canine mammary carcinomas, implicating LEF1 in ligand-independent activation of canonical Wnt signaling in canine mammary tumors. We conclude that canonical Wnt activation may be a frequent event in canine mammary tumors both through Wnt ligand-dependent and novel ligand-independent mechanisms.

  13. Tumor-associated macrophages: Oblivious confederates in invasive mammary carcinoma

    Directory of Open Access Journals (Sweden)

    Imtiaz Ahmed

    2017-01-01

    Full Text Available Background: The infiltrating margins of carcinomas are associated with presence of inflammatory cell infiltrate which are an integral part of the tumor microenvironment. Amongst the inflammatory cells, Tumor Associated Macrophages (TAMs play a key role in the tumorigenesis. This study elucidates the density of TAMs in invasive mammary carcinomas and attempts to establish aa association with the following pathological variables: tumor size, histological grade, nodal status, hormonal expression status and Her2Neu overexpression. Materials and Methods: 90 diagnosed archival cases of invasive mammary carcinomas at a tertiary care centre were included. Density of TAMs was assessed by using CD68 which is a pan-macrophage marker by immunohistochemistry on the archival tissue blocks. The density TAMs (CD68 positive cells was dichotomised into high (>50 CD68 positive cells/ HPF and low (<5050 CD68 positive cells/ HPF and compared with the above mentioned pathological variables using appropriate statistical tests. Results: The density of TAMs was significantly higher around the infiltrating edge of the carcinoma in comparison to the adjoining normal terminal duct lobular units. The density of TAMs was more in the infiltrating edge of the tumor than within the tumor nodule/nests. A higher TAM density showed a significant association in tumors having large tumor size, higher histological grade, nodal metastasis, absence of ER and PR expression and Her2Neu overexpression (p value <0.05. Conclusion: TAMs play an important role in tumor progression in invasive mammary carcinomas. This is as a result of the multiple roles enacted by TAMs in the various stages of tumor development starting from tumor growth, invasion, angiogenesis and metastases. Targeted therapy against TAMs has great potential in the being important components of future treatment strategies against breast carcinomas.

  14. Misregulation of Stromelysin-1 in Mouse Mammary Tumor Cells Accompanies Acquisition of Stromelysin-1 dependent Invasive Properties

    Energy Technology Data Exchange (ETDEWEB)

    Lochter, A.; Srebrow, A.; Sympson, C.J.; Terracio, N.; Werb, Z.; Bissell, M.J.

    1997-02-21

    Stromelysin-1 is a member of the metalloproteinase family of extracellular matrix-degrading enzymes that regulates tissue remodeling. We previously established a transgenic mouse model in which rat stromelysin-1 targeted to the mammary gland augmented expression of endogenous stromelysin-1, disrupted functional differentiation, and induced mammary tumors. A cell line generated from an adenocarcinoma in one of these animals and a previously described mammary tumor cell line generated in culture readily invaded both a reconstituted basement membrane and type I collagen gels, whereas a nonmalignant, functionally normal epithelial cell line did not. Invasion of Matrigel by tumor cells was largely abolished by metalloproteinase inhibitors, but not by inhibitors of other proteinase families. Inhibition experiments with antisense oligodeoxynucleotides revealed that Matrigel invasion of both cell lines was critically dependent on stromelysin-1 expression. Invasion of collagen, on the other hand, was reduced by only 40-50%. Stromelysin-1 was expressed in both malignant and nonmalignant cells grown on plastic substrata. Its expression was completely inhibited in nonmalignant cells, but up-regulated in tumor cells, in response to Matrigel. Thus misregulation of stromelysin-1 expression appears to be an important aspect of mammary tumor cell progression to an invasive phenotype. The matrix metalloproteinases (MMPs) are a family of extracellular matrix (ECM)-degrading enzymes that have been implicated in a variety of normal developmental and pathological processes, including tumorigenesis. The MMP family comprises at least 15 members with different, albeit overlapping, substrate specificities. During activation of latent MMPs, their propeptides are cleaved and they are converted to a lower molecular weight form by other enzymes, including serine proteinases, and by autocatalytic cleavage. Among the MMPs, stromelysin-1 (SL1) possesses the broadest substrate specificity. Despite

  15. Radiogenic neoplasia in thyroid and mammary clonogens

    International Nuclear Information System (INIS)

    Clifton, K.H.

    1991-01-01

    We have developed rat thyroid and mammary clonogen transplantation systems for the study of radiogenic cancer induction at the target cell level in vivo. The epithelial cell populations of both glands contain small subpopulations of cells which are capable of giving rise to monoclonal glandular structures when transplanted and stimulated with appropriate hormones. During the end of the last grant year and the first half of the current grant year, we have completed analyses and summarized for publication: investigations on the relationship between grafted thyroid cell number and the rapidity and degree of reestablishment of the thyroid-hypothalamicpituitary axis in thyroidectomized rats maintained on a normal diet or an iodine deficient diet; studies of the persistence of, and the differentiation potential and functional characteristics of, the TSH- (thyrotropin-) responsive sub-population of clonogens during goitrogenesis, the plateau-phase of goiter growth, and goiter involution; studies of changes in the size of the clonogen sub-population during goitrogenesis, goiter involution and the response to goitrogen rechallenge; and the results of the large carcinogenesis experiment on the nature of the grafted thyroid cell number-dependent suppression of promotion/progression to neoplasia in grafts of radiation-initiated thyroid cells. We are testing new techniques for the culture, cytofluorescent analysis and characterization mammary epithelial cells and of clonogens in a parallel project, and plan to apply similar technology to the thyroid epithelial cells and clonogen population. Data from these studies will be used in the design of future carcinogenesis experiments on neoplastic initiation by high and low LET radiations and on cells interactions during the neoplastic process

  16. Role of the Stem Cell Niche in Hormone-induced Tumorigenesis in Fetal Mouse Mammary Epithelium

    National Research Council Canada - National Science Library

    Chepko, Gloria; Hilakivi-Clarke, Leena

    2006-01-01

    Develop an immunohistochemical method for identifying stem cells and stem cell niches, and to use this to determine if in utero estrogenic overstimulation causes changes in the number of stem cells or their niches...

  17. Twisted Gastrulation as a BMP Modulator during Mammary Gland Development and Tumorigenesis

    Science.gov (United States)

    2014-05-01

    tissues ( Bonilla -Claudio et al., 2012). In WT TEBs (Fig. 8A–D) and mature ducts (Fig. 8I–L) almost all luminal cells expressed GATA-3. In contrast, Twsg1...PubMed: 12952901] Bonilla -Claudio M, Wang J, Bai Y, Klysik E, Selever J, Martin JF. Bmp signaling regulates a dosedependent transcriptional...deficient mice. Arch Oral Biol. 2006; 51:433–8. [PubMed: 16289463] Metallo CM, Ji L, de Pablo JJ, Palecek SP. Retinoic Acid and Bone Morphogenetic

  18. Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein.

    Directory of Open Access Journals (Sweden)

    Yuanyuan Li

    Full Text Available Breast cancer is one of the most lethal diseases in women; however, the precise etiological factors are still not clear. Genistein (GE, a natural isoflavone found in soybean products, is believed to be a potent chemopreventive agent for breast cancer. One of the most important mechanisms for GE inhibition of breast cancer may involve its potential in impacting epigenetic processes allowing reversal of aberrant epigenetic events during breast tumorigenesis. To investigate epigenetic regulation for GE impedance of breast tumorigenesis, we monitored epigenetic alterations of several key tumor-related genes in an established breast cancer transformation system. Our results show that GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21(WAF1 (p21 and p16(INK4a (p16, although it decreased expression of two tumor promoting genes, BMI1 and c-MYC. GE treatment led to alterations of histone modifications in the promoters of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes. In addition, an orally-fed GE diet prevented breast tumorigenesis and inhibited breast cancer development in breast cancer mice xenografts. Our results suggest that genistein may repress early breast tumorigenesis by epigenetic regulation of p21 and p16 by impacting histone modifications as well as the BMI1-c-MYC complex recruitment to the regulatory region in the promoters of these genes. These studies will facilitate more effective use of soybean product in breast cancer prevention and also help elucidate the mechanisms during the process of early breast tumorigenesis.

  19. Epigenetic regulation of multiple tumor-related genes leads to suppression of breast tumorigenesis by dietary genistein.

    Science.gov (United States)

    Li, Yuanyuan; Chen, Huaping; Hardy, Tabitha M; Tollefsbol, Trygve O

    2013-01-01

    Breast cancer is one of the most lethal diseases in women; however, the precise etiological factors are still not clear. Genistein (GE), a natural isoflavone found in soybean products, is believed to be a potent chemopreventive agent for breast cancer. One of the most important mechanisms for GE inhibition of breast cancer may involve its potential in impacting epigenetic processes allowing reversal of aberrant epigenetic events during breast tumorigenesis. To investigate epigenetic regulation for GE impedance of breast tumorigenesis, we monitored epigenetic alterations of several key tumor-related genes in an established breast cancer transformation system. Our results show that GE significantly inhibited cell growth in a dose-dependent manner in precancerous breast cells and breast cancer cells, whereas it exhibited little effect on normal human mammary epithelial cells. Furthermore, GE treatment increased expression of two crucial tumor suppressor genes, p21(WAF1) (p21) and p16(INK4a) (p16), although it decreased expression of two tumor promoting genes, BMI1 and c-MYC. GE treatment led to alterations of histone modifications in the promoters of p21 and p16 as well as the binding ability of the c-MYC-BMI1 complex to the p16 promoter contributing to GE-induced epigenetic activation of these tumor suppressor genes. In addition, an orally-fed GE diet prevented breast tumorigenesis and inhibited breast cancer development in breast cancer mice xenografts. Our results suggest that genistein may repress early breast tumorigenesis by epigenetic regulation of p21 and p16 by impacting histone modifications as well as the BMI1-c-MYC complex recruitment to the regulatory region in the promoters of these genes. These studies will facilitate more effective use of soybean product in breast cancer prevention and also help elucidate the mechanisms during the process of early breast tumorigenesis.

  20. Mammary carcinoma diagnostics and therapy; Diagnostik und Therapie des Mammakarzinoms

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, Uwe; Baum, Friedemann (eds.) [Diagnostisches Brustzentrum Goettingen BZG, Goettingen(Germany)

    2014-11-01

    The book on mammary carcinoma diagnostics and therapy covers the following issues: development, anatomy and physiology of the mammary glands, pathology of benign and malign mammary gland changes, non-imaging diagnostics; mammography; ultrasonic mammography; magnetic resonance tomography of the mammary glands; imaging diagnostics findings; mammary interventions; examination concepts; operative therapy of the mammary carcinoma; chemotherapy of the mammary carcinoma; radio-oncological therapy of the mammary carcinoma; logistics in a medical center for mammary gland diseases; logistics in an interdisciplinary center for mammary diseases; dialogue conduction and psycho-social attendance.

  1. Breast Cancer and Early Onset Childhood Obesity: Cell Specific Gene Expression in Mammary Epithelia and Adipocytes

    Science.gov (United States)

    2007-07-01

    G, Lee AV, McCarty M, Van Horn K, Chu O, Chou YC, Yang J, Guzman RC, Nandi S, Talamantes F. Growth and characterization of N-methyl-N- nitrosourea ...G, Lee AV, McCarty M, et al. Growth and characteriza- tion of N-methyl-N- nitrosourea -induced mammary tumors in intact and ovariectomized rats

  2. CDB-4124, a progesterone receptor modulator, inhibits mammary carcinogenesis by suppressing cell proliferation and inducing apoptosis.

    Science.gov (United States)

    Wiehle, Ronald; Lantvit, Daniel; Yamada, Tohru; Christov, Konstantin

    2011-03-01

    CDB-4124 (Proellex or telapristone acetate) is a modulator of progesterone receptor (PR) signaling, which is currently employed in preclinical studies for prevention and treatment of breast cancer and has been used in clinical studies for treatment of uterine fibroids and endometriosis. Here we provide evidence for its action on steroid hormone-signaling, cell cycle-regulated genes and in vivo on mammary carcinogenesis. When CDB-4124 is given to rats at 200 mg/kg for 24 months, it prevents the development of spontaneous mammary hyperplastic and premalignant lesions. Also, CDB-4124 given as subcutaneous pellets at two different doses suppressed, dose dependently, N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis. The high dose (30 mg, over 84 days) increased tumor latency from 66 ± 24 days to 87 ± 20 days (P CDB-4124 inhibited cell proliferation and induced apoptosis in MNU-induced mammary tumors, which correlated with a decreased proportion of PR(+) tumor cells and with decreased serum progesterone. CDB-4124 did not affect serum estradiol. In a mechanistic study employing T47D cells we found that CDB-4124 suppressed G(1)/G(0)-S transition by inhibiting CDK2 and CDK4 expressions, which correlated with inhibition of estrogen receptor (ER) expression. Taken together, these data indicate that CDB-4124 can suppress the development of precancerous lesions and carcinogen-induced ER(+) mammary tumors in rats, and may have implications for prevention and treatment of human breast cancer.

  3. Evidence for an association between increased oxidative stress and derangement of FOXO1 signaling in tumorigenesis of a cellular angiofibroma with monoallelic 13q14: a case report.

    Science.gov (United States)

    Arakaki, Kazunari; Chinen, Katsuya; Kamiya, Masuzo; Tanabe, Yasuka; Tawata, Natsumi; Ikehara, Fukino; Uehara, Karina; Shimabukuro, Hiroichi; Kinjo, Takao

    2014-01-01

    Cellular angiofibroma (CAF) is a rare soft tissue tumor characterized by random arrangement of spindle tumor cells in the stroma with short collagen bundles and thick- and hyalinized small vessels. CAFs share histological characteristics with spindle cell lipomas and mammary type myofibroblastomas. Because these tumors harbor monoallelic 13q14, common genetic and molecular mechanism for tumorigenesis is presumed. In this study, we reported a case of CAF in a 69-year-old man with monoallelic 13q14. Immunohistochemical analysis revealed that FOXO1, which is located in chromosome 13q14, was not expressed in the tumor. We also detected oxidative stress markers and found p38 MAPK activation, which is often induced by cellular stressors such as reactive oxygen species (ROS). Because FOXO1 induces the expression of genes encoding enzymes that generate antioxidants, oxidative stress induced by loss of FOXO1 expression may be common among CAFs, spindle cell lipomas, and mammary type myofibroblastomas.

  4. Histopathological and in vivo evidence of regucalcin as a protective molecule in mammary gland carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Marques, Ricardo; Vaz, Cátia V.; Maia, Cláudio J. [CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã (Portugal); Gomes, Madalena [IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto (Portugal); Gama, Adelina [Department of Veterinary Sciences, Animal and Veterinary Science Research Center (CECAV), University of Trás-os-Montes and Alto Douro (UTAD) (Portugal); Alves, Gilberto; Santos, Cecília R. [CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã (Portugal); Schmitt, Fernando [IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto (Portugal); Medical Faculty, University of Porto, Porto (Portugal); Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto (Canada); Department of Pathology, University Health Network, Toronto (Canada); Socorro, Sílvia, E-mail: ssocorro@fcsaude.ubi.pt [CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã (Portugal)

    2015-01-15

    Regucalcin (RGN) is a calcium-binding protein, which has been shown to be underexpressed in cancer cases. This study aimed to determine the association of RGN expression with clinicopathological parameters of human breast cancer. In addition, the role of RGN in malignancy of mammary gland using transgenic rats overexpressing the protein (Tg-RGN) was investigated. Wild-type (Wt) and Tg-RGN rats were treated with 7,12-dimethylbenz[α]anthracene (DMBA). Carcinogen-induced tumors were histologically classified and the Ki67 proliferation index was estimated. Immunohistochemistry analysis showed that RGN immunoreactivity was negatively correlated with the histological grade of breast infiltrating ductal carcinoma suggesting that progression of breast cancer is associated with loss of RGN. Tg-RGN rats displayed lower incidence of carcinogen-induced mammary gland tumors, as well as lower incidence of invasive forms. Moreover, higher proliferation was observed in non-invasive tumors of Wt animals comparatively with Tg-RGN. Overexpression of RGN was associated with diminished expression of cell-cycle inhibitors and increased expression of apoptosis inducers. Augmented activity of apoptosis effector caspase-3 was found in the mammary gland of Tg-RGN. RGN overexpression protected from carcinogen-induced mammary gland tumor development and was linked with reduced proliferation and increased apoptosis. These findings indicated the protective role of RGN in the carcinogenesis of mammary gland. - Highlights: • RGN immunoreactivity was negatively correlated with breast cancer differentiation. • Transgenic overexpression of RGN diminished incidence of carcinogen-induced tumors. • Transgenic overexpression of RGN restricted proliferation and fostered apoptosis. • RGN has a protective role in the carcinogenesis of mammary gland.

  5. NF-kappaB in Lung Tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Cai, Zhenjian [Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, New York University School of Medicine, 462 First Avenue, NBV 7N24, New York, NY 10016 (United States); Tchou-Wong, Kam-Meng; Rom, William N., E-mail: william.rom@nyumc.org [Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, New York University School of Medicine, 462 First Avenue, NBV 7N24, New York, NY 10016 (United States); Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987 (United States)

    2011-12-14

    The development of lung cancer in humans can be divided into three steps initiation, promotion and progression. This process is driven by alterations in related signal transduction pathways. These pathways signal the aberrant activation of NF-kappaB, a transcription factor that regulates the expression of genes important for lung tumorigenesis. Our current knowledge about the role of the NF-kappaB signaling pathway in the development of lung cancer has been bolstered by animal models demonstrating the connection between K-ras and tobacco induced lung transformation with NF-kappaB. Activation of downstream genes leads to cell proliferation, inhibition of apoptosis, angiogenesis, inflammation, invasion, and metastasis.

  6. NF-kappaB in Lung Tumorigenesis

    International Nuclear Information System (INIS)

    Cai, Zhenjian; Tchou-Wong, Kam-Meng; Rom, William N.

    2011-01-01

    The development of lung cancer in humans can be divided into three steps initiation, promotion and progression. This process is driven by alterations in related signal transduction pathways. These pathways signal the aberrant activation of NF-kappaB, a transcription factor that regulates the expression of genes important for lung tumorigenesis. Our current knowledge about the role of the NF-kappaB signaling pathway in the development of lung cancer has been bolstered by animal models demonstrating the connection between K-ras and tobacco induced lung transformation with NF-kappaB. Activation of downstream genes leads to cell proliferation, inhibition of apoptosis, angiogenesis, inflammation, invasion, and metastasis

  7. Mammary and femoral hydatid cysts.

    Science.gov (United States)

    Shamim, Muhammad

    2010-08-01

    Hydatid cyst disease most commonly affects liver and lungs, but it can affect all viscera and soft tissues of the body. Simultaneous mammary and femoral hydatid cysts, without any other visceral involvement, are extremely rare. This is a case report of 25-years-old female, presenting with lump in left breast mimicking fibroadenoma and lump in right thigh mimicking fibroma. Both turned out to be hydatid cysts.

  8. Laminin and biomimetic extracellular elasticity enhance functional differentiation in mammary epithelia

    Energy Technology Data Exchange (ETDEWEB)

    Alcaraz, Jordi; Xu, Ren; Mori, Hidetoshi; Nelson, Celeste M.; Mroue, Rana; Spencer, Virginia A.; Brownfield, Doug; Radisky, Derek C.; Bustamante, Carlos; Bissell, Mina J.

    2008-10-20

    In the mammary gland, epithelial cells are embedded in a 'soft' environment and become functionally differentiated in culture when exposed to a laminin-rich extracellular matrix gel. Here, we define the processes by which mammary epithelial cells integrate biochemical and mechanical extracellular cues to maintain their differentiated phenotype. We used single cells cultured on top of gels in conditions permissive for {beta}-casein expression using atomic force microscopy to measure the elasticity of the cells and their underlying substrata. We found that maintenance of {beta}-casein expression required both laminin signalling and a 'soft' extracellular matrix, as is the case in normal tissues in vivo, and biomimetic intracellular elasticity, as is the case in primary mammary epithelial organoids. Conversely, two hallmarks of breast cancer development, stiffening of the extracellular matrix and loss of laminin signalling, led to the loss of {beta}-casein expression and non-biomimetic intracellular elasticity. Our data indicate that tissue-specific gene expression is controlled by both the tissues unique biochemical milieu and mechanical properties, processes involved in maintenance of tissue integrity and protection against tumorigenesis.

  9. Diverse bone morphogenetic protein expression profiles and smad pathway activation in different phenotypes of experimental canine mammary tumors.

    Directory of Open Access Journals (Sweden)

    Helena Wensman

    Full Text Available BACKGROUND: BMPs are currently receiving attention for their role in tumorigenesis and tumor progression. Currently, most BMP expression studies are performed on carcinomas, and not much is known about the situation in sarcomas. METHODOLOGY/PRINCIPAL FINDINGS: We have investigated the BMP expression profiles and Smad activation in clones from different spontaneous canine mammary tumors. Spindle cell tumor and osteosarcoma clones expressed high levels of BMPs, in particular BMP-2, -4 and -6. Clones from a scirrhous carcinoma expressed much lower BMP levels. The various clones formed different tumor types in nude mice but only clones that expressed high levels of BMP-6 gave bone formation. Phosphorylated Smad-1/5, located in the nucleus, was detected in tumors derived from clones expressing high levels of BMPs, indicating an active BMP signaling pathway and BMP-2 stimulation of mammary tumor cell clones in vitro resulted in activation of the Smad-1/5 pathway. In contrast BMP-2 stimulation did not induce phosphorylation of the non-Smad pathway p38 MAPK. Interestingly, an increased level of the BMP-antagonist chordin-like 1 was detected after BMP stimulation of non-bone forming clones. CONCLUSIONS/SIGNIFICANCE: We conclude that the specific BMP expression repertoire differs substantially between different types of mammary tumors and that BMP-6 expression most probably has a biological role in bone formation of canine mammary tumors.

  10. Mammary inflammation around parturition appeared to be attenuated by consumption of fish oil rich in n-3 polyunsaturated fatty acids.

    Science.gov (United States)

    Lin, Sen; Hou, Jia; Xiang, Fang; Zhang, Xiaoling; Che, Lianqiang; Lin, Yan; Xu, Shengyu; Tian, Gang; Zeng, Qiufeng; Yu, Bing; Zhang, Keying; Chen, Daiwen; Wu, De; Fang, Zhengfeng

    2013-12-31

    Mastitis endangers the health of domestic animals and humans, and may cause problems concerning food safety. It is documented that n-3 polyunsaturated fatty acids (PUFA) play significant roles in attenuating saturated fatty acids (SFA)-induced inflammation. This study was therefore conducted to determine whether mammary inflammation could be affected by consumption of diets rich in n-3 PUFA. Forty-eight rats after mating began to receive diets supplemented with 5% fish oil (FO) or 7% soybean oil (SO). Blood and mammary tissue samples (n = 6) at day 0 and 14 of gestation and day 3 postpartum were collected 9 hours after intramammary infusion of saline or lipopolysaccharide (LPS) to determine free fatty acids (FFA) concentration and FA composition in plasma and inflammation mediators in mammary tissues. At day 14 of gestation and day 3 postpartum, the FO-fed rats had lower plasma concentrations of C18:2n6, C20:4n6, total n-6 PUFA and SFA, and higher plasma concentrations of C20:5n3 and total n-3 PUFA than the SO-fed rats. Plasma C22:6n3 concentration was also higher in the FO-fed than in the SO-fed rats at day 3 postpartum. Compared with the SO-fed rats, the FO-fed rats had lower mammary mRNA abundance of xanthine oxidoreductase (XOR) and protein level of tumor necrosis factor (TNF)-α, but had higher mammary mRNA abundances of interleukin (IL)-10 and peroxisome proliferator-activated receptor (PPAR)-γ at day 14 of gestation. Following LPS infusion at day 3 postpartum, the SO-fed rats had increased plasma concentrations of FFA, C18:1n9, C18:3n3, C18:2n6 and total n-6 PUFA, higher mammary mRNA abundances of IL-1β, TNF-α and XOR but lower mammary mRNA abundance of IL-10 than the FO-fed rats. Mammary inflammation around parturition appeared to be attenuated by consumption of a diet rich in n-3 PUFA, which was associated with up-regulated expression of IL-10 and PPAR-γ.

  11. Mammographic manifestations of mammary hamartoma (with an analysis of 10 cases)

    International Nuclear Information System (INIS)

    Yu Cheng; Luo Zebin; Chen Yun; Lin Wenmiao; Diao Shenglin

    2006-01-01

    Objective: To analyze the mammographic characteristics and the pathological basis of mammary hamartoma. Methods: The mammogram of 10 cases of mammary hamartoma proved by pathology were retrospectively analyzed. The patients aged from 25 to 56 years with an average age of (40.1 ± 5.4 years ). Results: According to the fat/parenchyma ratio, the mammgraphic manifestations of mammary hamartoma were divided into three types. 2 highly radiolucent lesions were classified as fat type, 2 lesions with high density were classified as dense type and the rest 6 lesions were the mixed type composed of adipose and glandular tissue. The mixed type was the most distinctive, while the dense or rat type was easy to be misdiagnosed. Accurate diagnosis was made in 6 cases out of, and the overall diagnostic accuracy was 60%. Conclusion: Mammography is the choice of diagnosis, and an accurate diagnosis will help surgical planning. (authors)

  12. Radiogenic neoplasia in thyroid and mammary clonogens

    International Nuclear Information System (INIS)

    Clifton, K.H.

    1992-01-01

    We have developed rat thyroid and mammary clonogen transplantation systems for the study of radiogenic cancer induction at the target cell level in vivo. The epithelial cell populations of both glands contain small subpopulations of cells which are capable of giving rise to monoclonal glandular structures when transplanted and stimulated with appropriate hormones. Previous results indicated that these clonogens are the precursor cells of radiogenic cancer, and that initiation, is common event at the clonegenic cell level. Detailed information on the physiologic control of clonogen proliferation, differentiation, and total numbers is thus essential to an understanding of the carcinogenic process. We report here studies on investigations on the relationships between grafted thyroid cell number and the rapidity and degree of reestablishment of the thyroid-hypothalamus-pituitary feedback axis in thyroidectomized rats maintained on a normal diet or an iodine deficient diet; studies of the persistence of, and the differentiation potential and functional characteristics of, the TSH-(thyrotropin-) responsive sub- population of clonogens during goitrogenesis, the plateau-phase of goiter growth, and goiter involution; studies of changes in the size of the clonogen sub-population during goitrogenesis, goiter involution and the response to goitrogen rechallenge; and a large carcinogenesis experiment on the nature of the grafted thyroid cell number-dependent suppression of promotion/progression to neoplasia in grafts of radiation-initiated thyroid cells. Data from these studies will be used in the design of future carcinogenesis experiments on neoplastic initiation by high and low LET radiations and on cell interactions during the neoplastic process

  13. Human breast cancer: concerted role of diet, prolactin and adrenal C19-delta 5-steroids in tumorigenesis.

    Science.gov (United States)

    Adams, J B

    1992-04-01

    The low incidence of breast cancer in Japan disappears within 2 generations in migrant Japanese in the USA. This is of fundamental importance if we are to understand, and perhaps reverse, the high rate seen in Western countries. Diet is the most likely factor involved, and a review of the topic of diet, body mass index, and gain in adult body mass, supports a relationship between these factors and breast-cancer risk in post-menopausal, but not pre-menopausal, women. A direct link between nutritional factors and secretion of the hormones prolactin and dehydroepiandrosterone sulfate is proposed. An estrogen 5-androstene-3 beta, 17 beta-diol is formed peripherally from the latter steroid, and in Western women attains a blood concentration at which it is biologically active. Thus diet/fat provides factors, viz., fatty acids, prolactin and estrogen, which in concerted fashion provide a milieu conducive to mammary tumorigenesis.

  14. Possible mechanism of phthalates-induced tumorigenesis

    Directory of Open Access Journals (Sweden)

    Yu-Chih Wang

    2012-07-01

    Full Text Available Phthalates—substances used in the manufacture of plastics—are considered as possible human carcinogens and tumor-promoting agents. The worldwide annual production of plastics surpassed 300 million tons in 2010. Plastics are an indispensable material in modern society, and many products manufactured from plastics are a boon to public health; however, plastics also pose health risks. Animal studies have indicated that phthalates are carcinogenic, but human epidemiological data confirming this carcinogenicity in humans are limited. The activation of peroxisome proliferator-activated receptor α (PPARα, which has been observed in rodent carcinogenesis, has not been observed in humans. Here, we review the hypothesis that the aryl hydrocarbon receptor (AhR and its downstream signaling cascade promote phthalate-induced tumorigenesis.

  15. The role of menin in parathyroid tumorigenesis.

    LENUS (Irish Health Repository)

    Davenport, Colin

    2009-01-01

    Primary hyperparathyroidism is a common disorder that involves the pathological enlargement of one or more parathyroid glands resulting in excessive production of parathyroid hormone (PTH). The exact pathogenesis of this disease remains to be fully understood. In recent years interest has focussed on the interaction between menin protein and the transforming growth factor (TGF)-beta\\/Smad signalling pathway. In vitro experimentation has demonstrated that the presence of menin is required for TGF-beta to effectively inhibit parathyroid cell proliferation and PTH production. This observation correlates with the almost universal occurrence of parathyroid tumors accompanying the inactivation of menin in multiple endocrine neoplasia Type 1 (MEN1) syndrome and the high rate of somatic menin gene mutations seen in sporadic parathyroid adenomas. This chapter aims to review the role of menin in primary hyperparathyroidism and parathyroid hormone-regulation, including the influences of MEN1 gene mutations on parathyroid cell proliferation, differentiation and tumorigenesis.

  16. Breast metastases primitive extra mammary

    International Nuclear Information System (INIS)

    Terzieff, V.; Vázquez, A.; Alonso, I.; Sabini, G.

    2004-01-01

    Less than 3% of all breast cancers originate from a primitive extra mammary. In 40% of cases it is the first manifestation of the primitive properly studied but 80% are associated with widely disseminated disease. It typically presents as a nodule on external quadrant s painful in half the cases. The majority (60%) of metastases derived from breast contralateral breast tumors are believed to via the lymphatic system. of the ; extra mammary the most common tumors are melanoma; hematologic and neuroendocrine. Although some imaging characteristics can guide diagnosis is histological. Cytology has good performance in experienced hands; but up to 25% of cases there may be difficulty in establishing diagnosis. Treatment depends on the type of tumor. Mastectomy should not be practiced or axillary clearance routine as is generally the context of disease disseminated. Radiation therapy may be useful for local control. It has been proposed laser ablation but no experience with it. The overall prognosis is bad. For a man of 45 with a breast metastasis occurs only a clear cell carcinoma of the kidney

  17. Scaffold attachment factor B1 (SAFB1 heterozygosity does not influence Wnt-1 or DMBA-induced tumorigenesis

    Directory of Open Access Journals (Sweden)

    Lewis Michael T

    2009-03-01

    Full Text Available Abstract Background Scaffold Attachment Factor B1 (SAFB1 is a multifunctional protein which has been implicated in breast cancer previously. We recently generated SAFB1 knockout mice (SAFB1-/-, but pleiotropic phenotypes including high lethality, dwarfism associated with low IGF-I levels, and infertility and subfertility in male and female mice, respectively, do not allow for straightforward tumorigenesis studies in these mice. Therefore, we asked whether SAFB1 heterozygosity would influence tumor development and progression in MMTV-Wnt-1 oncomice or DMBA induced tumorigenicity, in a manner consistent with haploinsufficiency of the remaining allele. Methods We crossed female SAFB1+/- (C57B6/129 mice with male MMTV-Wnt-1 (C57B6/SJL mice to obtain SAFB1+/+/Wnt-1, SAFB1+/-/Wnt-1, and SAFB1+/- mice. For the chemical induced tumorigenesis study we treated 8 weeks old SAFB1+/- and SAFB+/+ BALB/c mice with 1 mg DMBA once per week for 6 weeks. Animals were monitored for tumor incidence and tumor growth. Tumors were characterized by performing H&E, and by staining for markers of proliferation and apoptosis. Results We did not detect significant differences in tumor incidence and growth between SAFB1+/+/Wnt-1 and SAFB1+/-/Wnt-1 mice, and between DMBA-treated SAFB1+/+ and SAFB1+/-mice. Histological evaluation of tumors showed that SAFB1 heterozygosity did not lead to changes in proliferation or apoptosis. There were, however, significant differences in the distribution of tumor histologies with an increase in papillary and cribriform tumors, and a decrease in squamous tumors in the SAFB1+/-/Wnt-1 compared to the SAFB1+/+/Wnt-1 tumors. Of note, DMBA treatment resulted in shortened survival of SAFB1+/- mice compared to their wildtype littermates, however this trend did not reach statistical significance. Conclusion Our data show that SAFB1 heterozygosity does not influence Wnt-1 or DMBA-induced mammary tumorigenesis.

  18. Adiponectin haploinsufficiency promotes mammary tumor development in MMTV-PyVT mice by modulation of phosphatase and tensin homolog activities.

    Directory of Open Access Journals (Sweden)

    Janice B B Lam

    Full Text Available Adiponectin is an adipokine possessing beneficial effects on obesity-related medical complications. A negative association of adiponectin levels with breast cancer development has been demonstrated. However, the precise role of adiponectin deficiency in mammary carcinogenesis remains elusive.In the present study, MMTV-polyomavirus middle T antigen (MMTV-PyVT transgenic mice with reduced adiponectin expressions were established and the stromal effects of adiponectin haploinsufficiency on mammary tumor development evaluated. In mice from both FVB/N and C57BL/6J backgrounds, insufficient adiponectin production promoted mammary tumor onset and development. A distinctive basal-like subtype of tumors, with a more aggressive phenotype, was derived from adiponectin haplodeficient MMTV-PyVT mice. Comparing with those from control MMTV-PyVT mice, the isolated mammary tumor cells showed enhanced tumor progression in re-implanted nude mice, accelerated proliferation in primary cultures, and hyperactivated phosphatidylinositol-3-kinase (PI3K/Akt/beta-catenin signaling, which at least partly attributed to the decreased phosphatase and tensin homolog (PTEN activities. Further analysis revealed that PTEN was inactivated by a redox-regulated mechanism. Increased association of PTEN-thioredoxin complexes was detected in tumors derived from mice with reduced adiponectin levels. The activities of thioredoxin (Trx1 and thioredoxin reductase (TrxR1 were significantly elevated, whereas treatment with either curcumin, an irreversible inhibitor of TrxR1, or adiponectin largely attenuated their activities and resulted in the re-activation of PTEN in these tumor cells. Moreover, adiponectin could inhibit TrxR1 promoter-mediated transcription and restore the mRNA expressions of TrxR1.Adiponectin haploinsufficiency facilitated mammary tumorigenesis by down-regulation of PTEN activity and activation of PI3K/Akt signalling pathway through a mechanism involving Trx1/TrxR1

  19. Circadian Rhythm Disruption Promotes Lung Tumorigenesis.

    Science.gov (United States)

    Papagiannakopoulos, Thales; Bauer, Matthew R; Davidson, Shawn M; Heimann, Megan; Subbaraj, Lakshmipriya; Bhutkar, Arjun; Bartlebaugh, Jordan; Vander Heiden, Matthew G; Jacks, Tyler

    2016-08-09

    Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Sox2 Suppresses Gastric Tumorigenesis in Mice

    Directory of Open Access Journals (Sweden)

    Abby Sarkar

    2016-08-01

    Full Text Available Sox2 expression marks gastric stem and progenitor cells, raising important questions regarding the genes regulated by Sox2 and the role of Sox2 itself during stomach homeostasis and disease. By using ChIP-seq analysis, we have found that the majority of Sox2 targets in gastric epithelial cells are tissue specific and related to functions such as endoderm development, Wnt signaling, and gastric cancer. Unexpectedly, we found that Sox2 itself is dispensable for gastric stem cell and epithelial self-renewal, yet Sox2+ cells are highly susceptible to tumorigenesis in an Apc/Wnt-driven mouse model. Moreover, Sox2 loss enhances, rather than impairs, tumor formation in Apc-deficient gastric cells in vivo and in vitro by inducing Tcf/Lef-dependent transcription and upregulating intestinal metaplasia-associated genes, providing a mechanistic basis for the observed phenotype. Together, these data identify Sox2 as a context-dependent tumor suppressor protein that is dispensable for normal tissue regeneration but restrains stomach adenoma formation through modulation of Wnt-responsive and intestinal genes.

  1. Mammary fibroadenoma in a lamb

    Science.gov (United States)

    Guvenc, Tolga; Yarim, Murat; Kabak, Yonca B.; Sozgen, Yuksel

    2007-01-01

    A fibroadenoma was diagnosed in the left udder of a 3-month-old female Chios lamb. No recurrence was observed after surgery. Grossly, the tumor had a whitish-gray lobular appearance, and the lobules were interlaced with thin septa. Microscopically, the tumor was composed of proliferating fibroepithelial tissue, including differentiated ducts lined by whorls and interlacing bundles of abundant loose fibrovascular stroma. Immunohistochemistry revealed the ductal epithelium to be positive for pancytokeratin (AE1/AE3) and loose fibrovascular stroma was positive for vimentin and basal cells covering the ductal epithelium of alpha-smooth-muscle actin. Immunostaining for the estrogen and progesterone receptors was negative. A diagnosis of mammary fibroadenoma was made based on the histological and immunohistochemical findings. PMID:17993758

  2. Gordon Research Conference on Mammary Gland Biology

    International Nuclear Information System (INIS)

    1989-01-01

    The 1989 conference was the tenth in the series of biennial Gordon Research Conferences on Mammary Gland Biology. Traditionally this conference brings together scientists from diverse backgrounds and experience but with a common interest in the biology of the mammary gland. Investigators from agricultural and medical schools, biochemists, cell and molecular biologists, endocrinologists, immunologists, and representatives from the emerging biotechnology industries met to discuss current concepts and results on the function and regulation of the normal and neoplastic mammary gland in a variety of species. Of the participants, approximately three-fourths were engaged in studying the normal mammary gland function, whereas the other quarter were engaged in studying the neoplastic gland. The interactions between scientists, clinicians, veterinarians examining both normal and neoplastic cell function serves to foster the multi-disciplinary goals of the conference and has stimulated many cooperative projects among participants in previous years

  3. Mammary gigantism and D-penicillamine.

    Science.gov (United States)

    Finer, N; Emery, P; Hicks, B H

    1984-09-01

    Mammary gigantism is a rare complication of D-penicillamine treatment. We report a further case with pathological and endocrine details together with a review of the seven cases previously reported and possible mechanisms.

  4. Tumor-Specific Immunotherapy of Mammary Cancer

    National Research Council Canada - National Science Library

    Ostrand-Rosenberg, Suzanne

    1998-01-01

    .... To enhance the activation of CD4(+) T helper cells, autologous mouse mammary tumor cells have been transfected with syngeneic MHC class II genes plus costimulatory and antigen presentation accessory molecules, including B7-1, B7-2...

  5. Metastatic mammary carcinoma in a cow

    Directory of Open Access Journals (Sweden)

    Manoela Marchezan Piva

    Full Text Available ABSTRACT: Mammary gland neoplasms in cattle are rarely observed in the field veterinary diagnostics routine. Therefore, the objective of this study is to report a metastatic mammary carcinoma in a fourteen-year-old Holstein cow in the state of Santa Catarina, Brazil. The animal was diagnosed by the field veterinarian with clinical mastitis that was unresponsive to treatment, and was euthanized due to the poor prognosis. At the necropsy, multiple yellow, firm, and sometimes friable nodules, ranging from 0.1 to 20cm were observed in all mammary glands, lymph nodes, kidneys, spleen, liver, pancreas, mediastinal lymph nodes, heart, and lungs. The final diagnosis of mammary carcinoma was established through the association of clinical, necropsy, histopathological, and immunohistochemical findings. Differential diagnoses included diseases such as bovine tuberculosis and chronic fungal or bacterial mastitis.

  6. Mammary Stem Cells: Premise, Properties, and Perspectives.

    Science.gov (United States)

    Lloyd-Lewis, Bethan; Harris, Olivia B; Watson, Christine J; Davis, Felicity M

    2017-08-01

    Adult mammary stem cells (MaSCs) drive postnatal organogenesis and remodeling in the mammary gland, and their longevity and potential have important implications for breast cancer. However, despite intense investigation the identity, location, and differentiation potential of MaSCs remain subject to deliberation. The application of genetic lineage-tracing models, combined with quantitative 3D imaging and biophysical methods, has provided new insights into the mammary epithelial hierarchy that challenge classical definitions of MaSC potency and behaviors. We review here recent advances - discussing fundamental unresolved properties of MaSC potency, dynamics, and plasticity - and point to evolving technologies that promise to shed new light on this intractable debate. Elucidation of the physiological mammary differentiation hierarchy is paramount to understanding the complex heterogeneous breast cancer landscape. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Soybean diet breast tumor incidence in irradiated rats

    International Nuclear Information System (INIS)

    Troll, W.; Wiesner, R.

    1980-01-01

    The relationship between feeding a diet rich in protease inhibitors and the reduction of mammary cancer induced by x-irradiation in Sprague-Dawley rats was examined. Of a total of 145 irradiated animals, 44% of the 45 rats fed a raw soybean diet containing a high concentration of protease inhibitor developed mammary tumors as compared to 74% of 50 rats fed a casein diet containing no protease inhibitor. Animals fed Purina rat chow which contained low levels of protease inhibitor exhibited a 70% mammary tumor incidence. No spontaneous neoplasms were found in any of the non-irradiated animals on the raw soybean diet whereas about 10% of the animals on the protease-free diet developed tumors. Thus, soybeans which are rich in protease inhibitors reduced the induction of mammary cancer in x-irradiated rats. This suggested that diets rich in protease inhibitors may contribute to reducing cancer incidence in man. (author)

  8. Radioimaging of human mammary carcinoma xenografts in nude mice with a new monoclonal antibody

    International Nuclear Information System (INIS)

    Senekowitsch, R.; Bode, W.; Kriegel, H.; Reidel, G.; Pabst, H.W.

    1986-01-01

    A female Wistar rat aged 33 days was immunized by repeated intraperitoneal injections of a cell suspension of mammary carcinoma for eight months. Spleen cells of the immunized rat were then fused with X63-Ag8.653, a mouse myeloma line. Hybridoma supernatants were screened by ELISA using cells of mammary carcinoma (MaCa) as target cells. Initially 72 hybridomas showed positive response with MaCa cells, but no cross-reaction with normal mammary tissue was seen. Clone Ma 10-11 was chosen for its stable growth in vitro and in ascitic fluid. Monoclonal antibody obtained from ascitic fluid induced by intraperitoneal injection of 10 7 hybridoma cell into BALB/c-nu/nu mice was separated from albumin and transferrin. After separation only one band positioned at 155000 MW on SDS-PAGE slabs was detected. Radiolabeling with 131 I was achieved with the Iodogen method, the efficiency of labeling was 88%. 1.85 MBq of the intact labeled rat antibody were injected into nude mice xenografted with human mammary carcinoma and scintigrams were obtained every 48 hours p.i. up to 15 days. Scintigraphic images permitted tumor detection at 3 days p.i., but good tumor localization needed 8 days p.i.. The tumor-to-blood ratios calculated after dissection of tumor-bearing mice in groups of 3 increased from 0.97 at day 3 to 3 at day 15 p.i.. No uptake of the antibody in other organs was found. The half-life of the whole body clearance of the rat immunoglobulin was 36 h. This is significantly shorter than the half-life found for mouse immunoglobulin in nude mice. (Author)

  9. Age-dependent change in biological characteristics of stem cells in radiation-induced mammary carcinogenesis

    International Nuclear Information System (INIS)

    Shimada, Yoshiya; Nishimura, Mayumi; Kakinuma, Shizuko; Imaoka, Tatsuhiko; Yasukawa-Barnes, Jane; Gould, Michael N.; Clifton, Kelly H.

    2003-01-01

    If you ask what types of cells are the targets for carcinogenesis, a popular answer would be that cancer arises from stem cells. Stem cells are cells that are capable of both self-renewal and generation of differentiated progenies. If the hypothesis of 'cancer as stem cell disease' is correct, the risk of carcinogenesis should be a function of the number of stem cells and their responsiveness of carcinogen-induced damage. In the present study, we addressed the feasibility of this hypothesis using the rat mammary carcinogenesis model. One of the important conclusions emerging from studies on atomic bomb survivors concerns age-related changes in the susceptibility to breast cancer. The relative risk of breast cancer is very high among women exposed to ionizing radiation before or during puberty, and it decreases thereafter. Little information is available, however, on age-related changes in the radiobiological nature of mammary stem cells. We examined age-associated changes in the number of mammary stem-like cells (clonogens) and their susceptibility to radiation in terms of cell death and carcinogenic initiation frequency. The results were as follows. (1) During the prepubertal period, the total number of mammary clonogens per rat increased exponentially with a population doubling time of ∼4 days. After puberty, the doubling time lengthened to ∼30 days. The total number of clonogens in abdominal and inguinal mammary glands was ∼200 in 2-week-old rats, while it was ∼5600 in 8-week-old rats. (2) The survival curves of clonogenic cells after irradiation indicated that radiation sensitivity of the cells before and during puberty was much higher than after puberty. (3) The initiation frequency of the clonogens from prepubertal rats after 5 Gy irradiation was four times higher than that of the clonogens from post-pubertal rats. These results suggest that changes in the number of stem cells and their radiobiological characteristics underlie the age

  10. Age-dependent change in biological characteristics of stem cells in radiation-induced mammary carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Yoshiya; Nishimura, Mayumi; Kakinuma, Shizuko; Imaoka, Tatsuhiko [National Institute of Radiological Sciences, Anagawa, Chiba (Japan); Yasukawa-Barnes, Jane; Gould, Michael N.; Clifton, Kelly H. [Univ. of Wisconsin, Department of Human Oncology, Madison, WI (United States)

    2003-07-01

    If you ask what types of cells are the targets for carcinogenesis, a popular answer would be that cancer arises from stem cells. Stem cells are cells that are capable of both self-renewal and generation of differentiated progenies. If the hypothesis of 'cancer as stem cell disease' is correct, the risk of carcinogenesis should be a function of the number of stem cells and their responsiveness of carcinogen-induced damage. In the present study, we addressed the feasibility of this hypothesis using the rat mammary carcinogenesis model. One of the important conclusions emerging from studies on atomic bomb survivors concerns age-related changes in the susceptibility to breast cancer. The relative risk of breast cancer is very high among women exposed to ionizing radiation before or during puberty, and it decreases thereafter. Little information is available, however, on age-related changes in the radiobiological nature of mammary stem cells. We examined age-associated changes in the number of mammary stem-like cells (clonogens) and their susceptibility to radiation in terms of cell death and carcinogenic initiation frequency. The results were as follows. (1) During the prepubertal period, the total number of mammary clonogens per rat increased exponentially with a population doubling time of {approx}4 days. After puberty, the doubling time lengthened to {approx}30 days. The total number of clonogens in abdominal and inguinal mammary glands was {approx}200 in 2-week-old rats, while it was {approx}5600 in 8-week-old rats. (2) The survival curves of clonogenic cells after irradiation indicated that radiation sensitivity of the cells before and during puberty was much higher than after puberty. (3) The initiation frequency of the clonogens from prepubertal rats after 5 Gy irradiation was four times higher than that of the clonogens from post-pubertal rats. These results suggest that changes in the number of stem cells and their radiobiological characteristics

  11. Prolactin, TNF alpha and nitric oxide expression in nitroso-N-methylurea-induced-mammary tumours

    Directory of Open Access Journals (Sweden)

    Vegh Irene

    2007-11-01

    Full Text Available Abstract Background The N-Nitrosomethylurea breast cancer model induced in rats is used for the study of carcinogenesis in mammary cancer, prostate, pancreas, etc. This model is very similar to human neoplastic disease. Methods The present experimental study was designed to assess whether metoclopramide administration has any effect on development of MNU-induced tumours, and evaluate the treatment of goserelin acetate on PRL, TNF alpha and NO expression. NMU was administered to female Wistar rats on 2 occasions (5 mg/100 g body w/rat. PRL and TNF alpha were performed by immune-assay. Nitric Oxide by semi automated-assay and ploidy analyses by flow cytometry. Results The administration of metoclopramide made the induction time shorter and increased the incidence and average of tumours per rat. Tumours development was inhibited by a goserelin chronic administration. The ploidy of adenocarcinoma was polyploid-aneuploid type (average S = 60%. It was higher basal PRL plasma levels in rats with NMU induced tumours than in basal controls without tumour (p Conclusion The increase of blood PRL levels in NMU-induced rats may be an indicator of a poor prognosis of mammary cancer evolution. The metoclopramide administration accelerates tumour growth. However goserelin administration achieves regression in tumour development associated to inhibition PRL, TNF alpha and NO expression.

  12. Mammary gland involution is associated with rapid down regulation of major mammary Ca**2+-ATPases

    Science.gov (United States)

    Sixty percent of calcium in milk is transported across the mammary cells apical membrane by the plasma membrane Ca**2+-ATPase 2 (PMCA2). The effect of abrupt cessation of milk production on the Ca**2+-ATPases and mammary calcium transport is unknown. We found that 24 hours after stopping milk prod...

  13. Physiological Levels of Pik3ca H1047R Mutation in the Mouse Mammary Gland Results in Ductal Hyperplasia and Formation of ERα-Positive Tumors

    Science.gov (United States)

    Tikoo, Anjali; Roh, Vincent; Montgomery, Karen G.; Ivetac, Ivan; Waring, Paul; Pelzer, Rebecca; Hare, Lauren; Shackleton, Mark; Humbert, Patrick; Phillips, Wayne A.

    2012-01-01

    PIK3CA, the gene coding for the p110α subunit of phosphoinositide 3-kinase, is frequently mutated in a variety of human tumors including breast cancers. To better understand the role of mutant PIK3CA in the initiation and/or progression of breast cancer, we have generated mice with a conditional knock-in of the common activating mutation, Pik3caH1047R, into one allele of the endogenous gene in the mammary gland. These mice developed a ductal anaplasia and hyperplasia by 6 weeks of age characterized by multi-layering of the epithelial lining of the mammary ducts and expansion of the luminal progenitor (Lin−; CD29lo; CD24+; CD61+) cell population. The Pik3caH1047R expressing mice eventually develop mammary tumors with 100% penetrance but with a long latency (>12 months). This is significantly longer than has been reported for transgenic models where expression of the mutant Pik3ca is driven by an exogenous promoter. Histological analysis of the tumors formed revealed predominantly ERα-positive fibroadenomas, carcinosarcomas and sarcomas. In vitro induction of Pik3caH1047R in immortalized mammary epithelial cells also resulted in tumor formation when injected into the mammary fat pad of immunodeficient recipient mice. This novel model, which reproduces the scenario of a heterozygous somatic mutation occurring in the endogenous PIK3CA gene, will thus be a valuable tool for investigating the role of Pik3caH1047R mutation in mammary tumorigenesis both in vivo and in vitro. PMID:22666336

  14. Physiological levels of Pik3ca(H1047R mutation in the mouse mammary gland results in ductal hyperplasia and formation of ERα-positive tumors.

    Directory of Open Access Journals (Sweden)

    Anjali Tikoo

    Full Text Available PIK3CA, the gene coding for the p110α subunit of phosphoinositide 3-kinase, is frequently mutated in a variety of human tumors including breast cancers. To better understand the role of mutant PIK3CA in the initiation and/or progression of breast cancer, we have generated mice with a conditional knock-in of the common activating mutation, Pik3ca(H1047R, into one allele of the endogenous gene in the mammary gland. These mice developed a ductal anaplasia and hyperplasia by 6 weeks of age characterized by multi-layering of the epithelial lining of the mammary ducts and expansion of the luminal progenitor (Lin(-; CD29(lo; CD24(+; CD61(+ cell population. The Pik3ca(H1047R expressing mice eventually develop mammary tumors with 100% penetrance but with a long latency (>12 months. This is significantly longer than has been reported for transgenic models where expression of the mutant Pik3ca is driven by an exogenous promoter. Histological analysis of the tumors formed revealed predominantly ERα-positive fibroadenomas, carcinosarcomas and sarcomas. In vitro induction of Pik3ca(H1047R in immortalized mammary epithelial cells also resulted in tumor formation when injected into the mammary fat pad of immunodeficient recipient mice. This novel model, which reproduces the scenario of a heterozygous somatic mutation occurring in the endogenous PIK3CA gene, will thus be a valuable tool for investigating the role of Pik3ca(H1047R mutation in mammary tumorigenesis both in vivo and in vitro.

  15. Pleural radio guide exploration of the internal mammary chain

    International Nuclear Information System (INIS)

    Castillo, R. del; Clavijo, J.C.; Garello, N.C.; Pierotti, E.; Castillo, S. del

    2003-01-01

    Sentinel node technique permits to observe the compromise axillary and the internal mammary chain. The patients were marked with Technetium 99 peritumoral. The ganglion state of the mammary chain provides information of the estate of the breast cancer [es

  16. Mammary gland immunity and mastitis susceptibility.

    Science.gov (United States)

    Sordillo, Lorraine M; Streicher, Katie L

    2002-04-01

    Lactation is considered the final phase of the mammalian reproductive cycle, and the mammary gland provides milk for nourishment and disease resistance to the newborn. However, the cellular and soluble immune components associated with mammary tissues and secretion also can play an important role in protecting the gland from infectious diseases, such as mastitis. Mastitis can affect essentially all lactating mammals, but is especially problematic for dairy cattle. The most recent estimates from the National Mastitis Council suggest that mastitis affects one third of all dairy cows and will cost the dairy industry over 2 billion dollars annually in the United States in lost profits (National Mastitis Council (1996) Current Concepts in Bovine Mastitis, National Mastitis Council, Madison, WI). The overall impact of mastitis on the quality and quantity of milk produced for human consumption has provided the impetus to better understand the pathophysiology of the mammary gland and develop ways to enhance disease resistance through immunoregulation. As such, the bovine species has played a critical and prominent role in our current understanding of mammary gland immunobiology. This paper provides a comprehensive overview of mammary gland immunity and how the stage of lactation can impact important host defenses While this review emphasizes the bovine system, comparisons to humans and other domestic mammals will be addressed as well.

  17. Of Microenvironments and Mammary Stem Cells

    Energy Technology Data Exchange (ETDEWEB)

    LaBarge, Mark A; Petersen, Ole W; Bissell, Mina J

    2007-06-01

    In most adult tissues there reside pools of stem and progenitor cells inside specialized microenvironments referred to as niches. The niche protects the stem cells from inappropriate expansion and directs their critical functions. Thus guided, stem cells are able to maintain tissue homeostasis throughout the ebb and flow of metabolic and physical demands encountered over a lifetime. Indeed, a pool of stem cells maintains mammary gland structure throughout development, and responds to the physiological demands associated with pregnancy. This review discusses how stem cells were identified in both human and mouse mammary glands; each requiring different techniques that were determined by differing biological needs and ethical constraints. These studies together create a robust portrait of mammary gland biology and identify the location of the stem cell niche, elucidate a developmental hierarchy, and suggest how the niche might be manipulated for therapeutic benefit.

  18. Disturbance of Mammary UDP-Glucuronosyltransferase Represses Estrogen Metabolism and Exacerbates Experimental Breast Cancer.

    Science.gov (United States)

    Zhou, Xueyan; Zheng, Ziqiang; Xu, Chang; Wang, Juan; Min, Mengjun; Zhao, Yun; Wang, Xi; Gong, Yinhan; Yin, Jiale; Guo, Meng; Guo, Dong; Zheng, Junnian; Zhang, Bei; Yin, Xiaoxing

    2017-08-01

    The progression of breast cancer is closely related to the levels of estrogens within the body. UDP-glucuronosyltransferase (UGT) is an important class of phase II metabolizing enzymes, playing a pivotal role in detoxifying steroid hormone. In the present study, we aim at uncovering the potential dysregulation pattern of UGT and its role in estrogen metabolism and in the pathogenesis of breast cancer. Female Sprague-Dawley rats were treated with 100 mg/kg dimethylbenz(a)anthracene (DMBA) to induce breast cancer. Our results showed that the expression and activity of UGT in mammary tissues were downregulated significantly in DMBA rats. Consistent with this, levels of estradiol, 4-hydroxylated estradiol, and 2-hydroxylated estradiol were increased in both mammary tissues and serum, supporting a notable accumulation of toxic estrogen species in the target tissue of breast cancer. In addition, we also observed the decreased cell migration, cell proliferation, and DNA damage in UGT-transfected MCF-7 cells, suggesting a protective role of UGT against estrogen-induced mammary carcinogenesis. Taken together, these results indicated that accumulation of estrogens induced by UGT deficiency is a critical factor to induce the development of breast cancer. UGT contributes to estrogen elimination, and its glucuronidation capacity influences the estrogen signaling pathway and the pathogenesis of breast cancer. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  19. Cyclic-glycine-proline accelerates mammary involution by promoting apoptosis and inhibiting IGF-1 function.

    Science.gov (United States)

    Singh-Mallah, Gagandeep; McMahon, Christopher D; Guan, Jian; Singh, Kuljeet

    2017-12-01

    In rodents, post-lactational involution of mammary glands is characterized by the loss of mammary epithelial cells via apoptosis, which is associated with a decline in the expression of insulin-like growth factor-1 (IGF-1). Overexpression of IGF-1 delays involution by inhibiting apoptosis of epithelial cells and preserving the remaining secretory alveoli. Cyclic-glycine-proline (cGP), a metabolite of IGF-1, normalizes IGF-1 function under pathological conditions by regulating the bioavailability of IGF-1. The present study investigated the effect of cGP on the physiological decline in IGF-1 function during post-lactational mammary involution. Rat dams were gavaged with either cGP (3 mg/kg) or saline once per day from post-natal d8-22. Before collecting tissue on post-natal d23, a pair of mammary glands were sealed on d20 (72 hr-engorgement, thus representative of late-involution) and d22 (24 hr-engorgement, thus representative of mid-involution), while the remaining glands were allowed to involute naturally (early-involution). During early-involution, cGP accelerated the loss of mammary cells through apoptosis, resulting in an earlier clearance of intact secretory alveoli compared with the control group. This coincided with an earlier up-regulation of the cell survival factors, Bcl-xl and IGF-1R, in the early-involution cGP glands compared with the control glands. During late-involution, cGP reduced the bioactivity of IGF-1, which was evident through decreased phosphorylation of IGF-1R in the regressed alveoli. Maternal administration of cGP did not alter milk production and composition during early-, peak-, or late-stage of lactation. These data show that cGP accelerates post-lactational involution by promoting apoptosis and the physiological decline in IGF-1 function. © 2017 Wiley Periodicals, Inc.

  20. The Role of the Rab Coupling Protein in ErbB2-Driven Mammary Tumorigenesis and Metastasis

    Science.gov (United States)

    2015-10-01

    SOW-Task 1.Attain ethical approval from ACURO for the use of mice (Months 2-3) Evolution. Completion: 100%. To follow the ethical approval from...Western blotting were purchased from Biobasic, Bioshop and Sigma Aldrich respectively. Herceptin was purchased from Genetech. 7.16.4 murine antibody was...staining. Lung metastases were counted manually using Scanscope microscope software. DNA Plasmids and shRNAs— pcDNA3.0-His-RCP (a gift from Jim Norman

  1. Disruption of a Quorum Sensing mechanism triggers tumorigenesis: a simple discrete model corroborated by experiments in mammary cancer stem cells

    Directory of Open Access Journals (Sweden)

    Kirnasovsky Oleg U

    2010-04-01

    Full Text Available Abstract Background The balance between self-renewal and differentiation of stem cells is expected to be tightly controlled in order to maintain tissue homeostasis throughout life, also in the face of environmental hazards. Theory, predicting that homeostasis is maintained by a negative feedback on stem cell proliferation, implies a Quorum Sensing mechanism in higher vertebrates. Results Application of this theory to a cellular automata model of stem cell development in disrupted environments shows a sharply dichotomous growth dynamics: maturation within 50-400 cell cycles, or immortalization. This dichotomy is mainly driven by intercellular communication, low intensity of which causes perpetual proliferation. Another driving force is the cells' kinetic parameters. Reduced tissue life span of differentiated cells results in uncontrolled proliferation. Model's analysis, showing that under the Quorum Sensing control, stem cell fraction within a steady state population is fixed, is corroborated by experiments in breast carcinoma cells. Experimental results show that the plating densities of CD44+ cells and of CD44+/24lo/ESA+ cells do not affect stem cell fraction near confluence. Conclusions This study suggests that stem cell immortalization may be triggered by reduced intercellular communication, rather than exclusively result from somatic evolution, and implies that stem cell proliferation can be attenuated by signal manipulation, or enhanced by cytotoxics targeted to differentiated cells. In vivo verification and identification of the Quorum Sensing mediating molecules will pave the way to a higher level control of stem cell proliferation in cancer and in tissue engineering. Reviewers This article was reviewed by Glenn Webb and Marek Kimmel.

  2. Does Skeletal Muscle Mass Influence Breast Cancer? Evaluating Mammary Tumorigenesis and Progression Genetically Hyper-Muscular Mice

    Science.gov (United States)

    2006-07-01

    the skeletal muscle-specific muscle growth inhibitor myostatin and mice expressing a dominant negative form of the myostatin receptor, Activin...and rates of breast cancer initiation and progression. 15. SUBJECT TERMS Breast cancer, skeletal muscle, myostatin , MPA, DMBA, Activin receptor 16...including interleukins, Insulin-like Growth Factor (IGF) isoforms, IGF-binding proteins and myostatin . To determine the effect of skeletal muscle mass

  3. Does Skeletal Muscle Mass Influence Breast Cancer? Evaluating Mammary Tumorigenesis and Progression Genetically Hyper-Muscular Mice

    National Research Council Canada - National Science Library

    Zimmers, Teresa

    2006-01-01

    .... Mice lacking the skeletal muscle-specific muscle growth inhibitor myostatin and mice expressing a dominant negative form of the myostatin receptor, Activin Receptor Type IIB, display heightened muscle mass...

  4. Juvenile mammary papillomatosis; Papilomatosis juvenil mamaria

    Energy Technology Data Exchange (ETDEWEB)

    Alvarez, M.; Jimenez, A. V. [Hospital Reina Sofia. Cordoba (Spain)

    2001-07-01

    Juvenile mammary papillomatosis is a benign proliferative disease of young patients, generally under 30 years of age. The most frequent clinical presentation is the existence of an elastic and mobile lymph node of the breast. Anatomopathologically, it is characterized because it presents ductal epithelial hyperplasia, sometimes with marked atypia, and there are numerous cysts having different sizes among the findings. It has been associated with an increase in the incidence of breast cancer, both in the patient herself as well as her family. We review the literature on the subject and present the mammographic and ultrasonographic findings of a 22 year old woman diagnosed of juvenile mammary papillomatosis. (Author) 12 refs.

  5. CLINICOPATHOLOGIC FEATURES OF MAMMARY MASSES IN CAPTIVE LIONS (PANTHERA LEO).

    Science.gov (United States)

    Sadler, Ryan A; Craig, Linden E; Ramsay, Edward C; Helmick, Kelly; Collins, Darin; Garner, Michael M

    2016-03-01

    A multi-institutional retrospective analysis of 330 pathology accessions from 285 different lions found 15 captive, female African lions (Panthera leo) with confirmed mammary masses. Aside from the presence of a mammary mass, the most common initial clinical sign was inappetence. Histologic diagnoses were predominantly adenocarcinoma (n = 12), though two benign masses (mammary hyperplasia and a mammary cyst) and one squamous cell carcinoma were identified. Nine of 13 malignant tumors had metastasized to lymph nodes or viscera at the time of necropsy. Six lions with adenocarcinoma and two lions with benign mammary masses had received hormonal contraception, though little evidence of mammary lobular hyperplasia was seen in association with the adenocarcinomas. The most common concurrent disease processes found at necropsy were chronic urinary tract disease and other malignancies. These cases demonstrate that mammary malignancies occur in captive lions and frequently metastasize.

  6. MIBI-99mTc mammary scintigraphy

    International Nuclear Information System (INIS)

    Mayosky, Maria C.; Parma, Elvira P.; Armesto, Amparo M.; Zarlenga, Ana C.; Cresta, Carlos; Azar, Maria E.; Noblia, Cristina

    1999-01-01

    121 patients suspected of breast cancer were studied with MIBI- 99m Tc to evaluate the suitability of the mammary scintigraphy in patients with doubtful cancer diagnosis.The results show 93 % sensitivity and 95 % specificity and indicate the usefulness of this procedure to increase the accuracy of the diagnosis

  7. Does the correlation between EBNA-1 and p63 expression in breast carcinomas provide a clue to tumorigenesis in Epstein-Barr virus-related breast malignancies?

    Directory of Open Access Journals (Sweden)

    Ribeiro-Silva A.

    2004-01-01

    Full Text Available Several investigators have identified Epstein-Barr virus (EBV particles in breast carcinomas, a fact that supports a role for EBV in mammary tumorigenesis. The possible mechanism involved in this process is not clear. The present study was carried out in an attempt to determine whether there is a relationship between latent infection with EBV and p53 and p63 expression in breast carcinomas. Immunohistochemistry developed with 3.3-diaminobenzidine tetrahydrochloride was performed in 85 formalin-fixed paraffin-embedded breast carcinomas using anti-EBV EBNA-1, anti-p63, anti-p53, anti-estrogen receptor (ER and anti-progesterone receptor (PR antibodies. The cases were selected to represent each of the various histologic types: intraductal carcinoma (N = 12, grade I invasive ductal carcinoma (N = 15, grade II invasive ductal carcinoma (N = 15, grade III invasive ductal carcinoma (N = 15, tubular carcinoma (N = 8, lobular carcinoma (N = 10, and medullary carcinoma (N = 10. The ductal breast carcinomas were graded I, II and III based on the Scarff-Bloom and Richardson grading system modified by Elston and Ellis. One slide containing at least 1000 neoplastic cells was examined in each case. ER, PR, p63, p53 and EBNA-1 were positive in 60, 40, 11.8, 21.2 and 37.6% of carcinomas, respectively. There was a correlation between EBNA-1 and p63 expression (P < 0.001, but not between EBNA-1 and p53 (P = 0.10. These data suggest a possible role for p63 in the mammary tumorigenesis associated with Epstein-Barr virus infection.

  8. Efficacy of melatonin, IL-25 and siIL-17B in tumorigenesis-associated properties of breast cancer cell lines.

    Science.gov (United States)

    Gelaleti, Gabriela Bottaro; Borin, Thaiz Ferraz; Maschio-Signorini, Larissa Bazela; Moschetta, Marina Gobbe; Jardim-Perassi, Bruna Victorasso; Calvinho, Guilherme Berto; Facchini, Mariana Castilho; Viloria-Petit, Alicia M; de Campos Zuccari, Debora Aparecida Pires

    2017-08-15

    Mammary tumorigenesis can be modulated by melatonin, which has oncostatic action mediated by multiple mechanisms, including the inhibition of the activity of transcription factors such as NF-κB and modulation of interleukins (ILs) expression. IL-25 is an active cytokine that induces apoptosis in tumor cells due to differential expression of its receptor (IL-17RB). IL-17B competes with IL-25 for binding to IL-17RB in tumor cells, promoting tumorigenesis. This study purpose is to address the possibility of engaging IL-25/IL-17RB signaling to enhance the effect of melatonin on breast cancer cells. Breast cancer cell lines were cultured monolayers and 3D structures and treated with melatonin, IL-25, siIL-17B, each alone or in combination. Cell viability, gene and protein expression of caspase-3, cleaved caspase-3 and VEGF-A were performed by qPCR and immunofluorescence. In addition, an apoptosis membrane array was performed in metastatic cells. Treatments with melatonin and IL-25 significantly reduced tumor cells viability at 1mM and 1ng/mL, respectively, but did not alter cell viability of a non-tumorigenic epithelial cell line (MCF-10A). All treatments, alone and combined, significantly increased cleaved caspase-3 in tumor cells grown as monolayers and 3D structures (pmelatonin treatment. All treatments reduced VEGF-A protein expression in tumor cells (pmelatonin and IL-25-driven signaling in breast cancer cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. The properties of red seaweed (Kappaphycus alvarezii) and its effect on mammary carcinogenesis.

    Science.gov (United States)

    Chang, Vi-Sion; Okechukwu, Patrick N; Teo, Swee-Sen

    2017-03-01

    The edible red seaweed (Kappaphycus alvarezii) is one of the algae species which was found to be rich in nutrients and nutraceutical. Hence, K. alvarezii may have the ability to suppress cancer through its antiproliferative properties. The aim of this study was to investigate the potential compounds of K. alvarezii, cytotoxicity properties of K. alvarezii extract on breast cancer cell line (MCF-7), investigated toxicity effect of high dosage K. alvarezii extract in rats and determined the effect of K. alvarezii on 7, 12-dimethylbenz[a]anthracene (DMBA) mammary carcinogenesis in rats. The method of LCMS/MS and MTT assay were used. For animal study, sub-chronic toxicity method was used, the rats were supplemented with 2000mg/kg body weight daily of K. alvarezii crude extracts by oral gavage. For the anticancer effect of K. alvarezii crude extracts, this study consisted of three groups of the experimental, untreated and normal group of rats. The experimental and untreated groups of rats were induced with mammary tumour with DMBA. The experimental group of rats was given with K. alvarezii crude extracts orally. The results were being used to compare with the untreated group of rats and normal group of rats. All the rats were fed with standard diet and water ad libitum. Mortality, behavior changes and tumour sizes were observed specifically. The differences between the three groups of rats were evaluated by using the ANOVA test. By using LCMS/MS method, six unknown compounds were analysed. K. alvarezii crude extract reduced the cell viability of MCF-7 from 84.91% to 0.81% and the IC 50 value is 4.1±0.69mg/mL. For sub-chronic and heavy metal toxicity studies, no significant difference was found in haematological and biochemical values of the control group and experimental group. The growth rate of tumours in the untreated group of rats was found significantly higher than the experimental group of rats. Besides that, the white blood cells level in untreated group was

  10. Low doses of arsenic, via perturbing p53, promotes tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Ganapathy, Suthakar, E-mail: s.ganapathy@neu.edu [Center for Drug Development, Northeastern University, Boston (United States); Li, Ping [The First Affiliated Hospital, Zhengzhou University, Zhengzhou (China); The Institute of Clinic Sciences, Sahlgrenska Academy, Gothenburg (Sweden); Fagman, Johan [The Institute of Clinic Sciences, Sahlgrenska Academy, Gothenburg (Sweden); Yu, Tianqi; Lafontant, Jean [Center for Drug Development, Northeastern University, Boston (United States); Zhang, Guojun [The First Affiliated Hospital, Zhengzhou University, Zhengzhou (China); Chen, Changyan [Center for Drug Development, Northeastern University, Boston (United States); The Institute of Clinic Sciences, Sahlgrenska Academy, Gothenburg (Sweden)

    2016-09-01

    In drinking water and in workplace or living environments, low doses of arsenic can exist and operate as a potent carcinogen. Due to insufficient understanding and information on the pervasiveness of environmental exposures to arsenic, there is an urgent need to elucidate the underlying molecular mechanisms of arsenic regarding its carcinogenic effect on human health. In this study, we demonstrate that low doses of arsenic exposure mitigate or mask p53 function and further perturb intracellular redox state, which triggers persistent endoplasmic reticulum (ER) stress and activates UPR (unfolded protein response), leading to transformation or tumorigenesis. Thus, the results suggest that low doses of arsenic exposure, through attenuating p53-regulated tumor suppressive function, change the state of intracellular redox and create a microenvironment for tumorigenesis. Our study also provides the information for designing more effective strategies to prevent or treat human cancers initiated by arsenic exposure.

  11. Low doses of arsenic, via perturbing p53, promotes tumorigenesis

    International Nuclear Information System (INIS)

    Ganapathy, Suthakar; Li, Ping; Fagman, Johan; Yu, Tianqi; Lafontant, Jean; Zhang, Guojun; Chen, Changyan

    2016-01-01

    In drinking water and in workplace or living environments, low doses of arsenic can exist and operate as a potent carcinogen. Due to insufficient understanding and information on the pervasiveness of environmental exposures to arsenic, there is an urgent need to elucidate the underlying molecular mechanisms of arsenic regarding its carcinogenic effect on human health. In this study, we demonstrate that low doses of arsenic exposure mitigate or mask p53 function and further perturb intracellular redox state, which triggers persistent endoplasmic reticulum (ER) stress and activates UPR (unfolded protein response), leading to transformation or tumorigenesis. Thus, the results suggest that low doses of arsenic exposure, through attenuating p53-regulated tumor suppressive function, change the state of intracellular redox and create a microenvironment for tumorigenesis. Our study also provides the information for designing more effective strategies to prevent or treat human cancers initiated by arsenic exposure.

  12. Mechanisms of Reactive Stroma-Induced Tumorigenesis in Prostate Cancer

    Science.gov (United States)

    2016-11-01

    type I receptor blocker (SI Appendix, Fig. S9). Together, these results further support the concept that TGF-β1–expressing prostate cancer cells induce...of NBT-II bladder carcinoma cells to condi- tioned medium from normal fetal urogenital sinus. Cancer Res 47(11):2955–2960. 22. Nimmo R, Woollard A...AWARD NUMBER: W81XWH-12-1-0197 TITLE: Mechanisms of Reactive Stroma - Induced Tumorigenesis in Prostate Cancer PRINCIPAL INVESTIGATOR

  13. Evidence for systems-level molecular mechanisms of tumorigenesis

    Directory of Open Access Journals (Sweden)

    Capellá Gabriel

    2007-06-01

    Full Text Available Abstract Background Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth. Results Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs" defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree and global (betweenness and closeness measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis. Conclusion Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.

  14. Coexistence of tuberculosis and mammary carcinoma in a goat.

    Science.gov (United States)

    Quintas, H; Alegria, N; Mendonça, A; Botelho, A; Alves, A; Pires, I

    2014-08-01

    Synchronic occurrence of tuberculosis mastitis and mammary cancer is rare in humans and, to the best of our knowledge, not reported in domestic animals. Here, we present a case of a female adult goat of Serrana breed with simultaneous occurrence of a granulomatous mastitis, due to Mycobacterium caprae, and a mammary carcinoma. Both pathological conditions are rare in goats and should be included in differential diagnosis of mammary lesions. © 2014 Blackwell Verlag GmbH.

  15. Coexistence of tuberculosis and mammary carcinoma in a goat

    OpenAIRE

    Quintas, Hélder; Alegria, Nuno; Mendonça, Álvaro; Botelho, A.; Alves, A.; Pires, Isabel

    2014-01-01

    Synchronic occurrence of tuberculosis mastitis and mammary cancer is rare in humans and, to the best of our knowledge, not reported in domestic animals. Here, we present a case of a female adult goat of Serrana breed with simultaneous occurrence of a granulomatous mastitis, due to Mycobacterium caprae, and a mammary carcinoma. Both pathological conditions are rare in goats and should be included in differential diagnosis of mammary lesions. info:eu-repo/semantics/publishedVersion

  16. Labeled estrogens as mammary tumor probes

    International Nuclear Information System (INIS)

    Feenstra, A.

    1981-01-01

    In this thesis estrogens labeled with a gamma or positron emitting nuclide, called estrogen-receptor binding radiopharmaceuticals are investigated as mammary tumour probes. The requirements for estrogen-receptor binding radiopharmaceuticals are formulated and the literature on estrogens labeled for this purpose is reviewed. The potential of mercury-197/197m and of carbon-11 as label for estrogen-receptor binding radiopharmaceuticals is investigated. The synthesis of 197 Hg-labeled 4-mercury-estradiol and 2-mercury-estradiol and their properties in vitro and in vivo are described. It appears that though basically carbon-11 labeled compounds are very promising as mammary tumour probes, their achievable specific activity has to be increased. (Auth.)

  17. Mammary-type myofibroblastoma of soft tissue

    Directory of Open Access Journals (Sweden)

    Nebojsa Arsenovic

    2011-01-01

    Full Text Available A 40-year-old woman presented with a 1 year history of a painless, subcutaneous lump on the right buttock. Clinical examination showed an approximately 6 cm large subcutaneous mass covered by apparently normal-looking skin. No inguinal lymphadenopathy was found. The mass was excised with the clinical diagnosis of fibroma. Histologically, the lesion was consistent with mammary-type myofibroblastoma of soft tissue, a very rare, benign mesenchymal neoplasm with myofibroblastic differentiation. After surgical excision she was free of recurrence over a period of 8 months. This article also challenges the theory that suggests the origin of this tumor to be from the embryonic mammary tissue, adding another case of a site other than the milk lines.

  18. Ultrasound appearance of chronic mammary duct ectasia

    Energy Technology Data Exchange (ETDEWEB)

    Duchesne, N. [Ottawa Hospital, Dept. of Radiology, Ottawa, Ontario (Canada)]. E-mail: nathalie_duchesne_22@yahoo.ca; Skolnik, S. [Univ. of Toronto, Dept. of Family Medicine, Toronto, Ontario (Canada); Bilmer, S. [Ottawa Hospital, Dept. of Radiology, Ottawa, Ontario (Canada)

    2005-12-15

    Mammary duct ectasia (MDE), also called periductal mastitis, mammary dysplasia, or plasma cell mastitis, is a benign condition of the mammary gland first described by Haagensen in 1951. The etiology of MDE is unknown and its pathogenesis still controversial; the periductal inflammation could be either the cause or the result of dilated damaged ducts. The process is usually bilateral and asymptomatic, with only a small percentage of patients presenting with symptoms that may include long course of tumour formation, usually subareolar breast lumps, nipple discharge, nipple retraction, mastalgia, and mammary abscess or fistulas. Mammographic presentation of MDE is well known; its features include periductal calcification, benign intraductal calcification, and retroareolar duct dilatation. The periductal calcification results from dystrophic calcification and forms calcified rings or very dense, oval, elongated calcifications, each with a central lucency representing the dilated duct. Intraductal calcifications of duct ectasia represent inspissated intraductal material and are typically of uniform high density, often needle-like, and occasionally branching. Occasionally, there are no mammographic findings, and the diagnosis must rely on sonographic features. Appearance of MDE on ultrasonography (US) depends on the stage of the disease and the contents of the dilated ducts. The acute presentation has been demonstrated in the literature more often than has its chronic counterpart. In the former, duct content can vary from anechoic to isoechoic with surrounding fatty tissue. In chronic MDE, episodes of inflammation are longer. This tends to result in secretions that have a more solid, cheesy texture, partly due to cholesterol crystals, foam cells, and inflammatory cells. For both types of MDE, the appearance can mimic high-grade ductal carcinoma in situ (DCIS) on US. In this essay, 2 chronic MDE cases are presented and their US appearance discussed. Our goal is to explore

  19. Ultrasound appearance of chronic mammary duct ectasia

    International Nuclear Information System (INIS)

    Duchesne, N.; Skolnik, S.; Bilmer, S.

    2005-01-01

    Mammary duct ectasia (MDE), also called periductal mastitis, mammary dysplasia, or plasma cell mastitis, is a benign condition of the mammary gland first described by Haagensen in 1951. The etiology of MDE is unknown and its pathogenesis still controversial; the periductal inflammation could be either the cause or the result of dilated damaged ducts. The process is usually bilateral and asymptomatic, with only a small percentage of patients presenting with symptoms that may include long course of tumour formation, usually subareolar breast lumps, nipple discharge, nipple retraction, mastalgia, and mammary abscess or fistulas. Mammographic presentation of MDE is well known; its features include periductal calcification, benign intraductal calcification, and retroareolar duct dilatation. The periductal calcification results from dystrophic calcification and forms calcified rings or very dense, oval, elongated calcifications, each with a central lucency representing the dilated duct. Intraductal calcifications of duct ectasia represent inspissated intraductal material and are typically of uniform high density, often needle-like, and occasionally branching. Occasionally, there are no mammographic findings, and the diagnosis must rely on sonographic features. Appearance of MDE on ultrasonography (US) depends on the stage of the disease and the contents of the dilated ducts. The acute presentation has been demonstrated in the literature more often than has its chronic counterpart. In the former, duct content can vary from anechoic to isoechoic with surrounding fatty tissue. In chronic MDE, episodes of inflammation are longer. This tends to result in secretions that have a more solid, cheesy texture, partly due to cholesterol crystals, foam cells, and inflammatory cells. For both types of MDE, the appearance can mimic high-grade ductal carcinoma in situ (DCIS) on US. In this essay, 2 chronic MDE cases are presented and their US appearance discussed. Our goal is to explore

  20. Mammary-type myofibroblastoma of popliteal fossa

    International Nuclear Information System (INIS)

    Scotti, C.; Camnasio, F.; Fontana, F.; Fraschini, G.; Rizzo, N.; De Cobelli, F.; Peretti, G.M.

    2008-01-01

    Mammary-type myofibroblastoma is a very rare, benign, spindle cell lesion, arising mainly in the inguinal region. This clinical entity strictly duplicates the features of its breast counterpart. To our knowledge, this is the first report of this particular lesion occurring in the popliteal fossa. We discuss the clinical, radiological and histopathological features of this case, emphasizing the role of incisional biopsy in such an unusual neoplasia. (orig.)

  1. FRACTAL DIMENSIONALITY ANALYSIS OF MAMMARY GLAND THERMOGRAMS

    Directory of Open Access Journals (Sweden)

    Yu. E. Lyah

    2016-06-01

    Full Text Available Thermography may enable early detection of a cancer tumour within a mammary gland at an early, treatable stage of the illness, but thermogram analysis methods must be developed to achieve this goal. This study analyses the feasibility of applying the Hurst exponent readings algorithm for evaluation of the high dimensionality fractals to reveal any possible difference between normal thermograms (NT and malignant thermograms (MT.

  2. Global gene expression and morphological alterations in the mammary gland after gestational exposure to bisphenol A, genistein and indole-3-carbinol in female Sprague-Dawley offspring

    International Nuclear Information System (INIS)

    Grassi, Tony F.; Silva, Glenda N. da; Bidinotto, Lucas T.; Rossi, Bruna F.; Quinalha, Marília M.; Kass, Laura; Muñoz-de-Toro, Mónica; Barbisan, Luís F.

    2016-01-01

    This study aimed to evaluate the modifying effects of dietary genistein (GEN) and indole-3-carbinol (I3C) on early mammary gland development in female Sprague-Dawley offspring born to mothers exposed to BPA during gestation. Pregnant rats were treated with BPA25 or 250 μg/kg bw/day from gestational days 10 to 21 with or without dietary intake of GEN (250 mg/kg chow) or I3C (2000 mg/kg chow). At post-natal day (PND) 21, female offspring from different litters were euthanized for mammary gland development and gene expression analyses. Our results indicated that prenatal exposure to BPA25 and 250 did not modify the ductal elongation of the mammary gland tree or the estrogen receptor alpha (ER-α) expression in terminal end buds (TEBs). However, BPA25-exposed offspring had a higher number of terminal structures (TEBs + TDs) and an increased mammary branching and cell proliferation index in TEBs. Besides that, BPA25 and 250 modulated the expression of several genes in the immature mammary gland that were not changed in a dose dependent manner and involved different clusters of up- and down-regulated genes. Furthermore, BPA25 and BPA250 + I3C-treated groups also had a higher number of enriched functional gene categories. In addition, maternal dietary GEN and I3C in association with BPA exposure produced specific gene expression alterations in the mammary gland and overcome the adverse effect of BPA25, decreasing the branching of the mammary gland. In conclusion, prenatal BPA exposure induced both morphological and gene expression modifications on the mammary gland that dietary intake of GEN and I3C reverted on BPA25-exposed animals. - Highlights: • Gestational BPA and its association with GEN and I3C modify gene expression on the early mammary gland development. • GEN and I3C induced a different gene expression signature than lower BPA dose. • Dietary GEN and I3C countered the adverse effect of lower BPA dose on the cell proliferation and mammary gland development.

  3. Global gene expression and morphological alterations in the mammary gland after gestational exposure to bisphenol A, genistein and indole-3-carbinol in female Sprague-Dawley offspring

    Energy Technology Data Exchange (ETDEWEB)

    Grassi, Tony F. [UNESP – Univ. Estadual Paulista, Botucatu Medical School, Department of Pathology, Botucatu, SP (Brazil); Silva, Glenda N. da [UFOP – Federal University of Ouro Preto, Analysis Clinical Department, Ouro Preto, MG (Brazil); Bidinotto, Lucas T. [Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP (Brazil); Barretos School of Health Sciences, Dr. Paulo Prata - FACISB, Barretos, SP (Brazil); Rossi, Bruna F.; Quinalha, Marília M. [UNESP – Univ. Estadual Paulista, Botucatu Biosciences Institute, Department of Morphology, Botucatu, SP (Brazil); Kass, Laura; Muñoz-de-Toro, Mónica [UNL – Universidad Nacional del Litoral, School of Biochemistry and Biological Sciences, Human Pathology Department, Instituto de Salud y Ambiente del Litoral (ISAL, CONICET-UNL), Santa Fe (Argentina); Barbisan, Luís F., E-mail: barbisan@ibb.unesp.br [UNESP – Univ. Estadual Paulista, Botucatu Biosciences Institute, Department of Morphology, Botucatu, SP (Brazil)

    2016-07-15

    This study aimed to evaluate the modifying effects of dietary genistein (GEN) and indole-3-carbinol (I3C) on early mammary gland development in female Sprague-Dawley offspring born to mothers exposed to BPA during gestation. Pregnant rats were treated with BPA25 or 250 μg/kg bw/day from gestational days 10 to 21 with or without dietary intake of GEN (250 mg/kg chow) or I3C (2000 mg/kg chow). At post-natal day (PND) 21, female offspring from different litters were euthanized for mammary gland development and gene expression analyses. Our results indicated that prenatal exposure to BPA25 and 250 did not modify the ductal elongation of the mammary gland tree or the estrogen receptor alpha (ER-α) expression in terminal end buds (TEBs). However, BPA25-exposed offspring had a higher number of terminal structures (TEBs + TDs) and an increased mammary branching and cell proliferation index in TEBs. Besides that, BPA25 and 250 modulated the expression of several genes in the immature mammary gland that were not changed in a dose dependent manner and involved different clusters of up- and down-regulated genes. Furthermore, BPA25 and BPA250 + I3C-treated groups also had a higher number of enriched functional gene categories. In addition, maternal dietary GEN and I3C in association with BPA exposure produced specific gene expression alterations in the mammary gland and overcome the adverse effect of BPA25, decreasing the branching of the mammary gland. In conclusion, prenatal BPA exposure induced both morphological and gene expression modifications on the mammary gland that dietary intake of GEN and I3C reverted on BPA25-exposed animals. - Highlights: • Gestational BPA and its association with GEN and I3C modify gene expression on the early mammary gland development. • GEN and I3C induced a different gene expression signature than lower BPA dose. • Dietary GEN and I3C countered the adverse effect of lower BPA dose on the cell proliferation and mammary gland development.

  4. The non-protein coding breast cancer susceptibility locus Mcs5a acts in a non-mammary cell-autonomous fashion through the immune system and modulates T-cell homeostasis and functions.

    Science.gov (United States)

    Smits, Bart M G; Sharma, Deepak; Samuelson, David J; Woditschka, Stephan; Mau, Bob; Haag, Jill D; Gould, Michael N

    2011-08-16

    Mechanisms underlying low-penetrance, common, non-protein coding variants in breast cancer risk loci are largely undefined. We showed previously that the non-protein coding mammary carcinoma susceptibility locus Mcs5a/MCS5A modulates breast cancer risk in rats and women. The Mcs5a allele from the Wistar-Kyoto (WKy) rat strain consists of two genetically interacting elements that have to be present on the same chromosome to confer mammary carcinoma resistance. We also found that the two interacting elements of the resistant allele are required for the downregulation of transcript levels of the Fbxo10 gene specifically in T-cells. Here we describe mechanisms through which Mcs5a may reduce mammary carcinoma susceptibility. We performed mammary carcinoma multiplicity studies with three mammary carcinoma-inducing treatments, namely 7,12-dimethylbenz(a)anthracene (DMBA) and N-nitroso-N-methylurea (NMU) carcinogenesis, and mammary ductal infusion of retrovirus expressing the activated HER2/neu oncogene. We used mammary gland and bone marrow transplantation assays to assess the target tissue of Mcs5a activity. We used immunophenotyping assays on well-defined congenic rat lines carrying susceptible and resistant Mcs5a alleles to identify changes in T-cell homeostasis and function associated with resistance. We show that Mcs5a acts beyond the initial step of mammary epithelial cell transformation, during early cancer progression. We show that Mcs5a controls susceptibility in a non-mammary cell-autonomous manner through the immune system. The resistant Mcs5a allele was found to be associated with an overabundance of gd T-cell receptor (TCR)+ T-cells as well as a CD62L (L-selectin)-high population of all T-cell classes. In contrast to in mammary carcinoma, gdTCR+ T-cells are the predominant T-cell type in the mammary gland and were found to be overabundant in the mammary epithelium of Mcs5a resistant congenic rats. Most of them simultaneously expressed the CD4, CD8, and CD161

  5. Rats

    Directory of Open Access Journals (Sweden)

    Alexey Kondrashov

    2012-01-01

    Full Text Available We aimed to perform a chemical analysis of both Alibernet red wine and an alcohol-free Alibernet red wine extract (AWE and to investigate the effects of AWE on nitric oxide and reactive oxygen species production as well as blood pressure development in normotensive Wistar Kyoto (WKY and spontaneously hypertensive rats (SHRs. Total antioxidant capacity together with total phenolic and selected mineral content was measured in wine and AWE. Young 6-week-old male WKY and SHR were treated with AWE (24,2 mg/kg/day for 3 weeks. Total NOS and SOD activities, eNOS and SOD1 protein expressions, and superoxide production were determined in the tissues. Both antioxidant capacity and phenolic content were significantly higher in AWE compared to wine. The AWE increased NOS activity in the left ventricle, aorta, and kidney of SHR, while it did not change NOS activity in WKY rats. Similarly, increased SOD activity in the plasma and left ventricle was observed in SHR only. There were no changes in eNOS and SOD1 expressions. In conclusion, phenolics and minerals included in AWE may contribute directly to increased NOS and SOD activities of SHR. Nevertheless, 3 weeks of AWE treatment failed to affect blood pressure of SHR.

  6. Bovine mammary stem cells: Cell biology meets production agriculture

    Science.gov (United States)

    Mammary stem cells (MaSC) provide for net growth, renewal and turnover of mammary epithelial cells, and are therefore potential targets for strategies to increase production efficiency. Appropriate regulation of MaSC can potentially benefit milk yield, persistency, dry period management and tissue ...

  7. Construction of mammary gland specific expression plasmid pIN ...

    African Journals Online (AJOL)

    DR. NJ TONUKARI

    2012-04-03

    Apr 3, 2012 ... its function in expressing goat insulin-like growth factor 1 (IGF-1). The backbone ... Liver and mammary gland were harvested from Saanen dairy goats. ..... lactating mammary of goat, sheep and cattle found that αs1- and ...

  8. Epidemiology of a mammary glands cancer in Semipalatinsk region

    International Nuclear Information System (INIS)

    Arzykulov, Zh.A.; Kanaf'yanov, G.S.; Igisinov, S.I.; Sejtkazina, G.D.; Makhataeva, A.Zh.

    2003-01-01

    The tendency of mammary glands cancer morbidity for 1980-2000 years in the former Semipalatinsk test site has been studied. The trends of mammary glands cancer morbidity in dynamic are increase (T±5.4), moreover legalities have been presented in indices standardization for world standard

  9. Mammary Development and Breast Cancer: A Wnt Perspective

    Science.gov (United States)

    Yu, Qing Cissy; Verheyen, Esther M.; Zeng, Yi Arial

    2016-01-01

    The Wnt pathway has emerged as a key signaling cascade participating in mammary organogenesis and breast oncogenesis. In this review, we will summarize the current knowledge of how the pathway regulates stem cells and normal development of the mammary gland, and discuss how its various components contribute to breast carcinoma pathology. PMID:27420097

  10. The Possible Relationship Between Mammary Dysplasia and Breast ...

    African Journals Online (AJOL)

    Aim: There is need to resolve the continuing difficult question regarding the possible relationship between mammary dysplasia and breast cancer. Method: This is a 30-year study of the incidences of both mammary dysplasia and breast cancer occurring among the Igbos, a major ethnic group in Nigeria, West Africa. Results: ...

  11. Sonographic mammary gland density pattern in women in selected ...

    African Journals Online (AJOL)

    ... are known to affect the mammary gland density. This study aims to determine mammary gland density pattern in selected population of women in Sothern Nigeria using the American College of Radiology Imaging Reporting and Data System (ACR-BI-RADS) lexicon and to promote the use of ultrasound as a breast cancer ...

  12. Dosimetric evaluation of mammary tomosynthesis procedures

    International Nuclear Information System (INIS)

    Silva, Rayre Janaína Vieira; Perini, Ana Paula; Santos, William de Souza; Vedovato, Uly P.; Neves, Lucio Pereira

    2017-01-01

    This work presents the results of the research on the evaluation of radiation doses usually applied in mammary procedures, using the Monte Carlo method. A virtual environment was created, to mimic the procedures room, including the room, its components, patient and source. The spectrum was obtained from the literature. The percentage of energy deposited compared to energy deposited in the breast was determined, and the scattered radiation was absorbed in specific areas. The regions of the head and neck were the most affected by scattered radiation. (author)

  13. Mammary fibroadenoma with pleomorphic stromal cells.

    Science.gov (United States)

    Abid, Najla; Kallel, Rim; Ellouze, Sameh; Mellouli, Manel; Gouiaa, Naourez; Mnif, Héla; Boudawara, Tahia

    2015-01-01

    The presence of enlarged and pleomorphic nuclei is usually regarded as a feature of malignancy, but it may on occasion be seen in benign lesions such as mammary fibroadenomas. We present such a case of fibroadenoma occurring in a 37-year-old woman presenting with a self-palpable right breast mass. Histological examination of the tumor revealed the presence of multi and mononucleated giant cells with pleomorphic nuclei. The recognition of the benign nature of these cells is necessary for differential diagnosis from malignant lesions of the breast. fibroadenoma - pleomorphic stromal cells - atypia - breast.

  14. Postsurgical telecobalt radiotherapy of mammary carcinomas

    International Nuclear Information System (INIS)

    Liebl, R.

    1980-01-01

    The first part of the study is a literature survey. The second part deals with patients and results of radiotherapy of the Klinik and Poliklinik fuer Radiologie der Universitaet Muenchen. The patients with mammary carcinomas, who were treated between 1960 and 1969 were classified according to the TNM classification or they were attributed to stage I or II or III. When the therapy was begun, the mean age of the patients was 55 years, 80% of the patients was between 40 and 60 years old, 45% of the patients were in stage I, 35% in stage II and almost 20% in stage III. (orig./MG) [de

  15. Mammary gland pathologies in the parturient buffalo

    Directory of Open Access Journals (Sweden)

    G N Purohit

    2014-12-01

    Full Text Available Parturition related mammary gland pathologies in the buffalo appear to be low on accord of anatomic (longer teat length, thicker streak canal and physiologic (lower cisternal storage of secreted milk, lower milk production differences with cattle. Hemolactia, udder edema and hypogalactia usually occur in the buffalo due to physiologic changes around parturition however mastitis involves pathologic changes in the udder and teats; the incidence of mastitis is however lower compared to cattle. The incidence and therapy of hemolactia, udder edema and hypogalactia are mentioned and the risk factors, incidence, diagnosis, therapy and prevention for mastitis in buffalo are also described.

  16. Roles of p63 in epidermal development and tumorigenesis

    Directory of Open Access Journals (Sweden)

    Jeng-Yuan Yao

    2012-12-01

    Full Text Available pidermis is composed mainly of keratinocytes and is the ma­jor barrier of human body. The development and maintenance of normal epithelial structures and functions require the transcrip­tion factor p63. The p63 gene encodes proteins with structures simi­lar to that of p53, including an N-terminal transacti­vation (TA domain, a DNA-binding domain and a car­boxy-oligomerization domain. TAp63 and ΔNp63 (p63 isoforms without TA domain regulate a wide range of target genes that are important for embryonal development and epithelial integrity. Mutations of p63 gene cause epider­mal abnormalities characterized by ectodermal dysplasia. Recent reports have indicated that p63 plays important role in tumorigenesis as well. However, the relative importance of TAp63 and ΔNp63 in epidermal development and tumorigenesis re­mains mostly unclear and awaits further investigation. In this review, we summarize the current knowledge on the structure and function of p63 and its isoforms.

  17. Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Tao Xu

    2017-03-01

    Full Text Available Medulloblastoma is the most common malignant brain tumor in children. Therapeutic approaches to medulloblastoma (combination of surgery, radiotherapy, and chemotherapy have led to significant improvements, but these are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed. Genetic mutations leading to the activation of the Hedgehog pathway drive tumorigenesis in ~30% of medulloblastoma. In a yeast two-hybrid proteomic screen, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hedgehog signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the postphosphorylation fate of its targets. The GLI1/PIN1 interaction was validated by reciprocal pulldowns using epitope-tagged proteins in HEK293T cells as well as by co-immunoprecipiations of the endogenous proteins in a medulloblastoma cell line. Our results support a molecular model in which PIN1 promotes GLI1 protein abundance, thus contributing to the positive regulation of Hedgehog signals. Most importantly, in vivo functional analyses of Pin1 in the GFAP-tTA;TRE-SmoA1 mouse model of Hedgehog-driven medulloblastoma demonstrate that the loss of Pin1 impairs tumor development and dramatically increases survival. In summary, the discovery of the GLI1/PIN1 interaction uncovers PIN1 as a novel therapeutic target in Hedgehog-driven medulloblastoma tumorigenesis.

  18. Lysosomal enzyme activation in irradiated mammary tumors

    International Nuclear Information System (INIS)

    Clarke, C.; Wills, E.D.

    1976-01-01

    Lysosomal enzyme activity of C3H mouse mammary tumors was measured quantitatively by a histochemical method. Following whole-body doses of 3600 rad or less no changes were observed in the lysosomal enzyme activity for 12 hr after the irradiation, but very large increases in acid phosphatase and β-naphthylamidase activity were, however, observed 24 hr after irradiation. Significant increases in enzyme activity were detected 72 hr after a dose of 300 rad and the increases of enzyme activity were dose dependent over the range 300 to 900 rad. Testosterone (80 mg/kg) injected into mice 2 hr before irradiation (850 rad) caused a significant increase of lysosomal enzyme activity over and above that of the same dose of irradiation alone. If the tumor-bearing mice were given 95 percent oxygen/5 percent carbon dioxide to breathe for 8 min before irradiation the effect of 850 rad on lysosomal acid phosphatase was increased to 160 percent/that of the irradiation given alone. Activitation of lysosomal enzymes in mammary tumors is an important primary or secondary consequence of radiation

  19. Extra-mammary findings in breast MRI

    Energy Technology Data Exchange (ETDEWEB)

    Rinaldi, Pierluigi; Costantini, M.; Belli, P.; Giuliani, M.; Bufi, E.; Fubelli, R.; Distefano, D.; Romani, M.; Bonomo, L. [Catholic University - Policlinic A. Gemelli, Department of Bio-Imaging and Radiological Sciences, Rome (Italy)

    2011-11-15

    Incidental extra-mammary findings in breast Magnetic Resonance Imaging (MRI) may be benign in nature, but may also represent a metastasis or another important lesion. We aimed to analyse the prevalence and clinical relevance of these unexpected findings. A retrospective review of 1535 breast MRIs was conducted. Only axial sequences were reassessed. Confirmation examinations were obtained in all cases. 285 patients had a confirmed incidental finding, which were located in the liver (51.9%), lung (11.2%), bone (7%), mediastinal lymph nodes (4.2%) or consisted of pleural/pericardial effusion (15.4%). 20.4% of incidental findings were confirmed to be malignant. Positive predictive value for MRI to detect a metastatic lesion was high if located within the bone (89%), lymph nodes (83%) and lung (59%), while it was low if located within the liver (9%) or if it consisted of pleural/pericardial effusion (6%). The axial enhanced sequence showed superior sensitivity to unenhanced images in detecting metastatic lesions, especially if only smaller ({<=}10 mm.) lesions were considered. The prevalence of metastatic incidental extra-mammary findings is not negligible. Particular attention should be to incidental findings located within the lung, bone and mediastinal lymph nodes. (orig.)

  20. Induction of mammary gland tumor in female Sprague- Dawley rats ...

    African Journals Online (AJOL)

    STORAGESEVER

    2010-07-12

    Jul 12, 2010 ... The current methods for tumor induction in breast cancer research animal models are time-consuming, hazardous ... issue in animal has been a controversial and much disputed ..... to therapy and early detection of cancer.

  1. Radon-induced cancer: a cell-based model of tumorigenesis due to protracted exposures

    International Nuclear Information System (INIS)

    Elkind, M.M.

    1994-01-01

    In 1982, results with C3H mouse embryo cells showed that the frequency of neoplastic transformation was enhanced when exposures to fission-spectrum neutrons were protracted in time. This finding was unexpected because the opposite was found with low-LET radiations. Similar neutron enhancements were reported with normal life-span Syrian hamster embryo cells, and with human hybrid cells. Because other studies did not confirm the preceding, in 1990 - at a conference convened by the US Armed Forces Radiobiological Research Institute - a biophysical model was proposed to explain the basis for the enhancement observed in some experiments but not in others. The model attributed special sensitivities, related to killing and neoplastic transformation, to cells in and around mitosis. Subsequently, it was shown that late G 2 /M phase cells constituted this window of sensitivity. In the instance of tumorigenesis, the model predicted that protracted exposures to a high-LET radiation would result in enhanced frequencies of transformation providing that susceptible cells were cycling or could be induced to cycle. The model explained data on lung tumour induction in rats breathing radon at different concentrations, and uranium miners working in atmospheres containing different concentrations of radon. The model also explains the anomalous finding that lung cancer deaths are often sublinearly correlated with indoor radon concentration. (author)

  2. Intestinal tumorigenesis is not affected by progesterone signaling in rodent models.

    Directory of Open Access Journals (Sweden)

    Jarom Heijmans

    Full Text Available Clinical data suggest that progestins have chemopreventive properties in the development of colorectal cancer. We set out to examine a potential protective effect of progestins and progesterone signaling on colon cancer development. In normal and neoplastic intestinal tissue, we found that the progesterone receptor (PR is not expressed. Expression was confined to sporadic mesenchymal cells. To analyze the influence of systemic progesterone receptor signaling, we crossed mice that lacked the progesterone receptor (PRKO to the Apc(Min/+ mouse, a model for spontaneous intestinal polyposis. PRKO-Apc(Min/+ mice exhibited no change in polyp number, size or localization compared to Apc(Min/+. To examine effects of progestins on the intestinal epithelium that are independent of the PR, we treated mice with MPA. We found no effects of either progesterone or MPA on gross intestinal morphology or epithelial proliferation. Also, in rats treated with MPA, injection with the carcinogen azoxymethane did not result in a difference in the number or size of aberrant crypt foci, a surrogate end-point for adenoma development. We conclude that expression of the progesterone receptor is limited to cells in the intestinal mesenchyme. We did not observe any effect of progesterone receptor signaling or of progestin treatment in rodent models of intestinal tumorigenesis.

  3. Reconstitution of mammary epithelial morphogenesis by murine embryonic stem cells undergoing hematopoietic stem cell differentiation.

    Directory of Open Access Journals (Sweden)

    Shuxian Jiang

    2010-03-01

    Full Text Available Mammary stem cells are maintained within specific microenvironments and recruited throughout lifetime to reconstitute de novo the mammary gland. Mammary stem cells have been isolated through the identification of specific cell surface markers and in vivo transplantation into cleared mammary fat pads. Accumulating evidence showed that during the reformation of mammary stem cell niches by dispersed epithelial cells in the context of the intact epithelium-free mammary stroma, non-mammary epithelial cells may be sequestered and reprogrammed to perform mammary epithelial cell functions and to adopt mammary epithelial characteristics during reconstruction of mammary epithelium in regenerating mammary tissue in vivo.To examine whether other types of progenitor cells are able to contribute to mammary branching morphogenesis, we examined the potential of murine embryonic stem (mES cells, undergoing hematopoietic differentiation, to support mammary reconstitution in vivo. We observed that cells from day 14 embryoid bodies (EBs under hematopoietic differentiation condition, but not supernatants derived from these cells, when transplanted into denuded mammary fat pads, were able to contribute to both the luminal and myoepithelial lineages in branching ductal structures resembling the ductal-alveolar architecture of the mammary tree. No teratomas were observed when these cells were transplanted in vivo.Our data provide evidence for the dominance of the tissue-specific mammary stem cell niche and its role in directing mES cells, undergoing hematopoietic differentiation, to reprogram into mammary epithelial cells and to promote mammary epithelial morphogenesis. These studies should also provide insights into regeneration of damaged mammary gland and the role of the mammary microenvironment in reprogramming cell fate.

  4. Transplantation of β-endorphin neurons into the hypothalamus promotes immune function and restricts the growth and metastasis of mammary carcinoma.

    Science.gov (United States)

    Sarkar, Dipak K; Zhang, Changqing; Murugan, Sengottuvelan; Dokur, Madhavi; Boyadjieva, Nadka I; Ortigüela, Maria; Reuhl, Kenneth R; Mojtehedzadeh, Sepide

    2011-10-01

    Neurobehavioral stress has been shown to promote tumor growth and progression and dampen the immune system. In this study, we investigated whether inhibiting stress hormone production could inhibit the development of mammary carcinoma and metastasis in a rat model of breast carcinogenesis. To enhance β-endorphin (BEP), the endogenous opioid polypeptide that boosts immune activity and decreases stress, we generated BEP neurons by in vitro differentiation from fetal neuronal stem cells and transplanted them into the hypothalami of rats subjected to breast carcinogenesis. BEP-transplanted rats displayed a reduction in mammary tumor incidence, growth, malignancy rate, and metastasis compared with cortical cells-transplanted rats. BEP neuron transplants also reduced inflammation and epithelial to mesenchymal transition in the tumor tissues. In addition, BEP neuron transplants increased peripheral natural killer (NK) cell and macrophage activities, elevated plasma levels of antiinflammatory cytokines, and reduced plasma levels of inflammatory cytokines. Antimetastatic effects along with stimulation of NK cells and macrophages could be reversed by treatment with the opiate antagonist naloxone, the β-receptor agonist metaproterenol, or the nicotine acetylcholine receptor antagonist methyllycaconitine. Together, our findings establish a protective role for BEP against the growth and metastasis of mammary tumor cells by altering autonomic nervous system activities that enhance innate immune function.

  5. Condition of mammary glands in adolescent girls in Saratov region

    Directory of Open Access Journals (Sweden)

    Kunina A.V.

    2011-12-01

    Full Text Available The study was undertaken to estimate the condition of mammary glands in adolescent girls. Material and methods. The study included 867 girls (aged 12-18. The questioning, total clinical examination, hormonal analysis and ultrasound examination were conducted. Results. The investigation shows that girls had breast dysmorphies (macromastia, hypoplasia, striae, asymmetry etc.. The dysplasia of mammary glands was diagnosed in 26% patients with menstrual disorders, thyroid diseases, mastalgia and obesity. High estradiol, LH, TSH, insulin, cortisole, testosterone and low progesterone level are the most specific hormonal markers of mastopathy in adolescent girls. Conclusion. Thyroid disorders, breast asymmetric form, mastalgia, obesity are the indicators for observation and examination of mammary glands

  6. Breast Cancer Prevention by Hormonally Induced Mammary Gland Differentiation: The Role of a Novel Mammary Growth Inhibitor and Differentiation Factor MRG

    National Research Council Canada - National Science Library

    Shi, Y

    2000-01-01

    We have previously identified and characterized a novel tumor growth inhibitor and a fatty acid binding protein in human mammary gland and named it as Mammary derived growth inhibitor Related Gene MRG...

  7. Omega-3 Fatty Acids and a Novel Mammary Derived Growth Inhibitor Fatty Acid Binding Protein MRG in Suppression of Mammary Tumor

    National Research Council Canada - National Science Library

    Liu, Yiliang

    2001-01-01

    We have previously identified and characterized a novel tumor growth inhibitor and a fatty acid binding protein in human mammary gland and named it as Mammary derived growth inhibitor Related Gene MRG...

  8. Diverse microRNAs with convergent functions regulate tumorigenesis.

    Science.gov (United States)

    Zhu, Min-Yan; Zhang, Wei; Yang, Tao

    2016-02-01

    MicroRNAs (miRNAs) regulate several biological processes, including tumorigenesis. In order to comprehend the roles of miRNAs in cancer, various screens were performed to investigate the changes in the expression levels of miRNAs that occur in different types of cancer. The present review focuses on the results of five recent screens, whereby a number of overlapping miRNAs were identified to be downregulated or differentially regulated, whereas no miRNAs were observed to be frequently upregulated. Furthermore, the majority of the miRNAs that were common to >1 screen were involved in signaling networks, including wingless-related integration site, receptor tyrosine kinase and transforming growth factor-β, or in cell cycle checkpoint control. The present review will discuss the aforementioned miRNAs implicated in cell cycle checkpoint control and signaling networks.

  9. mTORC2 Promotes Tumorigenesis via Lipid Synthesis.

    Science.gov (United States)

    Guri, Yakir; Colombi, Marco; Dazert, Eva; Hindupur, Sravanth K; Roszik, Jason; Moes, Suzette; Jenoe, Paul; Heim, Markus H; Riezman, Isabelle; Riezman, Howard; Hall, Michael N

    2017-12-11

    Dysregulated mammalian target of rapamycin (mTOR) promotes cancer, but underlying mechanisms are poorly understood. We describe an mTOR-driven mouse model that displays hepatosteatosis progressing to hepatocellular carcinoma (HCC). Longitudinal proteomic, lipidomics, and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, leading to steatosis and tumor development. In particular, mTORC2 stimulated sphingolipid (glucosylceramide) and glycerophospholipid (cardiolipin) synthesis. Inhibition of fatty acid or sphingolipid synthesis prevented tumor development, indicating a causal effect in tumorigenesis. Increased levels of cardiolipin were associated with tubular mitochondria and enhanced oxidative phosphorylation. Furthermore, increased lipogenesis correlated with elevated mTORC2 activity and HCC in human patients. Thus, mTORC2 promotes cancer via formation of lipids essential for growth and energy production. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells

    International Nuclear Information System (INIS)

    Oka, Naoki; Soeda, Akio; Inagaki, Akihito; Onodera, Masafumi; Maruyama, Hidekazu; Hara, Akira; Kunisada, Takahiro; Mori, Hideki; Iwama, Toru

    2007-01-01

    There is increasing evidence for the presence of cancer stem cells (CSCs) in malignant brain tumors, and these CSCs may play a pivotal role in tumor initiation, growth, and recurrence. Vascular endothelial growth factor (VEGF) promotes the proliferation of vascular endothelial cells (VECs) and the neurogenesis of neural stem cells. Using CSCs derived from human glioblastomas and a retrovirus expressing VEGF, we examined the effects of VEGF on the properties of CSCs in vitro and in vivo. Although VEGF did not affect the property of CSCs in vitro, the injection of mouse brains with VEGF-expressing CSCs led to the massive expansion of vascular-rich GBM, tumor-associated hemorrhage, and high morbidity, suggesting that VEGF promoted tumorigenesis via angiogenesis. These results revealed that VEGF induced the proliferation of VEC in the vascular-rich tumor environment, the so-called stem cell niche

  11. Specitic gene alterations in radiation-induced tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Joo Mee; Kang, Chang Mo; Lee, Seung Sook; Cho, Chul Koo; Bae, Sang Woo; Lee, Su Jae; Lee, Yun Sil [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2004-07-01

    To identify a set of genes involved in the development of radiation-induced tumorigenesis, we used DNA microarrays consisting of 1,176 mouse genes and compared expression profiles of radioresistant cells, designated NIH3T3-R1 and -R4. These cells were tumorigenic in a nude mouse grafting system, as compared to the parental NIH3T3 cells. Expressions of MDM2, CDK6 and CDC25B were found to increase more than 3-fold. Entactin protein levels were downregulated in NIH3T3-R1 and -R4 cells. Changes in expression genes were confirmed by reverse transcription-PCR or western blotting. When these genes were transfected to NIH3T3 cells, the CDC25B and MDM2 overexpressing NIH3T3 cells showed radioresistance, while 2 CDK6 overexpressing cells did not. In the case of entactin overexpressing NIH3T3-R1 or R-4 cells were still radioresistant. Furthermore, the CDC25B and MDM2 overexpressing cells grafted to nude mice, were tumorigenic. NIH3T3-R1 and R4 cells showed increased radiation-induced apoptosis, accompanied by faster growth rate, rather than and earlier radiation-induced G2/M phase arrest, suggesting that the radioresistance of NIH3T3-R1 and R4 cells was due to faster growth rate, rather than induction of apoptosis. In the case of MDM2 and CDC25B overexpressing cells, similar phenomena, such as increased apoptosis and faster growth rate, were shown. The above results, therefore, demonstrate involvement of CDC25B and MDM2 overexpression in radiation-induced tumorigenesis and provide novel targets for detection of radiation-induced carcinogenesis.

  12. Aerosolized 3-bromopyruvate inhibits lung tumorigenesis without causing liver toxicity.

    Science.gov (United States)

    Zhang, Qi; Pan, Jing; North, Paula E; Yang, Shoua; Lubet, Ronald A; Wang, Yian; You, Ming

    2012-05-01

    3-Bromopyruvate, an alkylating agent and a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. However, the chemopreventive effect of 3-bromopyruvate in lung tumorigenesis has not been tested. In this study, we investigated the chemopreventive activity of 3-bromopyruvate in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and 3-bromopyruvate was administered by oral gavage to female A/J mice. We found that 3-bromopyruvate significantly decreased tumor multiplicity and tumor load by 58% and 83%, respectively, at a dose of 20 mg/kg body weight by gavage. Due to the known liver toxicity of 3-bromopyruvate in animal models given large doses of 3-bromopyruvate, confirmed in this study, we decided to test the chemopreventive activity of aerosolized 3-bromopyruvate in the same lung tumor model. As expected, aerosolized 3-bromopyruvate similarly significantly decreased tumor multiplicity and tumor load by 49% and 80%, respectively, at a dose of 10 mg/mL by inhalation. Interestingly, the efficacy of aerosolized 3-bromopyruvate did not accompany any liver toxicity indicating that it is a safer route of administering this compound. Treatment with 3-bromopyruvate increased immunohistochemical staining for cleaved caspase-3, suggesting that the lung tumor inhibitory effects of 3-bromopyruvate were through induction of apoptosis. 3-Bromopyruvate also dissociated hexokinase II from mitochondria, reduced hexokinase activity, and blocked energy metabolism in cancer cells, finally triggered cancer cell death and induced apoptosis through caspase-3, and PARP in human lung cancer cell line. The ability of 3-bromopyruvate to inhibit mouse lung tumorigenesis, in part through induction of apoptosis, merits further investigation of this compound as a chemopreventive agent for human lung cancer.

  13. Period 2 Mutation Accelerates ApcMin/+ Tumorigenesis

    Science.gov (United States)

    Wood, Patricia A.; Yang, Xiaoming; Taber, Andrew; Oh, Eun-Young; Ansell, Christine; Ayers, Stacy E.; Al-Assaad, Ziad; Carnevale, Kevin; Berger, Franklin G.; Peña, Maria Marjorette O.; Hrushesky, William J.M.

    2014-01-01

    Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 mutant (Per2m/m) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. We asked whether Per2 clock gene inactivation would accelerate intestinal and colonic tumorigenesis. The effects of PER2 on cell proliferation and β-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on β-catenin and on intestinal and colonic polyp formation were studied in mice with Per2 mutation alone and in combination with an Apc mutation using polyp-prone ApcMin/+ mice. Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases β-catenin, cyclin D, and cell proliferation. Down-regulation of β-catenin along with Per2 blocks the increase in cyclin D and cell proliferation. Per2m/m mice develop colonic polyps and show an increase in small intestinal mucosa β-catenin and cyclin D protein levels compared with wild-type mice. ApcMin/+Per2m/m mice develop twice the number of small intestinal and colonic polyps, with more severe anemia and splenomegaly, compared with ApcMin/+ mice. These data suggest that Per2 gene product suppresses tumorigenesis in the small intestine and colon by down-regulation of β-catenin and β-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control. PMID:19010825

  14. New and emerging factors in tumorigenesis: an overview

    Directory of Open Access Journals (Sweden)

    Kim S

    2015-07-01

    Full Text Available Suwon Kim1,2 1Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, 2Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA Abstract: This article provides an overview of the genes and cellular processes that have emerged recently as new key factors in tumorigenesis. We review these in the context of three broad categories. First, genome-scale sequencing studies have revealed a set of frequently mutated genes in cancer. Genes that are mutated in >5% of all cancers across tissue types are discussed, with a highlighted focus on the two most frequently mutated genes, TP53 and PIK3CA. Second, the mechanisms of resistance to targeted therapy are reviewed. These include acquired resistance under targeted therapy selection owing to mutations and amplification of genes in the same or parallel signaling pathways. Importantly, sequencing of primary tumors has revealed that therapy-resistant clones already exist prior to targeted therapy, demonstrating that tumor heterogeneity in primary tumors confers a mechanism for inherent therapy resistance. Third, “metastasis-specific genes”, or rather lack thereof, are discussed. While many genes have been shown to be capable of promoting metastasis in experimental systems, no common genetic alterations have been identified specific to metastatic lesions. Rather, the same gene mutations frequently found in primary tumors are also found prevalent in metastases, suggesting that the genes that drive tumorigenesis may also drive metastasis. In this light, an emerging view of metastatic progression is discussed. Collectively, these recent advances in cancer research have refined our knowledge on cancer etiology and progression but also present challenges that will require innovative new approaches to treat and manage cancer. Keywords: cancer, genomics, gene mutations, targeted therapy resistance, tumor heterogeneity, metastasis

  15. Advances in mammary imaging for forty years

    International Nuclear Information System (INIS)

    Maulmont, C. de; Cherel, P.; Ouhioun, O.; Becette, V.; Stevens, D.; Plantet, M.M.; Hagay, C.

    2000-01-01

    In the sixties years the mammary diagnosis is just clinical, then the low contrast mammography, not very efficient, appears in the seventies years. During the eighties years, the ultrasound is set up while modern mammography with high contrast allows the non palpable breast lesions diagnosis. In the nineties years the mammography come before the clinical examination within the context of the breast cancer screening program. Some histological correlation are more specific about the ductal carcinoma in situ grading with microcalcifications, while new techniques (MRI, CT) are evaluated. At present the stereotactic large core breast biopsies are benefit from the digital prone table, allow a histological diagnosis and avoid surgical excision of some indeterminate images. After the pernicious effects of imaging, we assess the progress according to the cancerous disease results. We also consider the problem of over-diagnosis and over-treatment of ductal carcinoma in situ. (author)

  16. An Anti-Oncogenic Role for Decorin in Mammary Carcinoma

    National Research Council Canada - National Science Library

    Iozzo, Renato V

    2004-01-01

    .... In the preliminary data that support the basis of this proposal, we discovered that decorin causes a functional inactivation of the oncogenic ErbB2 protein in mammary carcinoma cells overexpressing ErbB2...

  17. Molecular Markers of Metastasis in Ductal Mammary Carcinoma

    National Research Council Canada - National Science Library

    Achary, Patnala

    2002-01-01

    ...% of those patients, however, the disease spreads, and they are at risk of death. Our goal is to develop DNA markers that could be reliably used to identify the ductal mammary carcinomas that are prone to develop metastasis...

  18. Genomic and Phenomic Study of Mammary Pathogenic Escherichia coli

    Science.gov (United States)

    Blum, Shlomo E.; Heller, Elimelech D.; Sela, Shlomo; Elad, Daniel; Edery, Nir; Leitner, Gabriel

    2015-01-01

    Escherichia coli is a major etiological agent of intra-mammary infections (IMI) in cows, leading to acute mastitis and causing great economic losses in dairy production worldwide. Particular strains cause persistent IMI, leading to recurrent mastitis. Virulence factors of mammary pathogenic E. coli (MPEC) involved pathogenesis of mastitis as well as those differentiating strains causing acute or persistent mastitis are largely unknown. This study aimed to identify virulence markers in MPEC through whole genome and phenome comparative analysis. MPEC strains causing acute (VL2874 and P4) or persistent (VL2732) mastitis were compared to an environmental strain (K71) and to the genomes of strains representing different E. coli pathotypes. Intra-mammary challenge in mice confirmed experimentally that the strains studied here have different pathogenic potential, and that the environmental strain K71 is non-pathogenic in the mammary gland. Analysis of whole genome sequences and predicted proteomes revealed high similarity among MPEC, whereas MPEC significantly differed from the non-mammary pathogenic strain K71, and from E. coli genomes from other pathotypes. Functional features identified in MPEC genomes and lacking in the non-mammary pathogenic strain were associated with synthesis of lipopolysaccharide and other membrane antigens, ferric-dicitrate iron acquisition and sugars metabolism. Features associated with cytotoxicity or intra-cellular survival were found specifically in the genomes of strains from severe and acute (VL2874) or persistent (VL2732) mastitis, respectively. MPEC genomes were relatively similar to strain K-12, which was subsequently shown here to be possibly pathogenic in the mammary gland. Phenome analysis showed that the persistent MPEC was the most versatile in terms of nutrients metabolized and acute MPEC the least. Among phenotypes unique to MPEC compared to the non-mammary pathogenic strain were uric acid and D-serine metabolism. This study

  19. Immunohistochemical detection of estrogen receptors in canine mammary tumors

    OpenAIRE

    Elena Atanaskova Petrov; Ivica Gjurovski; Trpe Ristoski; Goran Nikolovski; Pandorce Trenkoska; Plamen Trojacanec; Ksenija Ilievska; Toni Dovenski; Gordana Petrushevska

    2016-01-01

    Mammary tumors are among the most common neoplasms in intact female dogs.They have a complex morphology, usually affecting middle age and older bitches. Almost 50% of the mammary tumors in dogs are malignant neoplasms. Prognosis is based on several factors: stage, age, tumor size, metastasis, histopathology, ovariectomy status and hormone-receptor activity. Immunohistochemical (IHC) measurement has become increasingly an important diagnostic and prognostic parameter, with the development of m...

  20. The Use of cDNA Microarray to Study Gene Expression in Wnt-1 Induced Mammary Tumors

    National Research Council Canada - National Science Library

    Huang, Shixia

    2002-01-01

    .... Specifically, we have collected tissue samples from virgin mammary glands, hyperplastic mammary glands, Wnt- 1 mammary tumors, and tumors metastasized to the lung, and compared their gene expression patterns...

  1. Radiogenic neoplasia in thyroid and mammary clonogens. Final progress report, 1 January 1987--31 December 1997

    Energy Technology Data Exchange (ETDEWEB)

    Clifton, K.H.

    1998-07-10

    The induction of cancer by ionizing radiation is a matter of great practical importance to the nuclear industry, to national defense, to radiological medicine and to the general public. It is increasingly apparent that carcinogenesis is a leading dose-limiting effect of radiation exposure. The thyroid and mammary glands are among the most sensitive human tissues to radiogenic initiation of cancer, and there is a profoundly higher risk of neoplastic initiation in these glands among individuals irradiated before or during puberty than among those exposed in later life. The authors developed unique quantitative experimental models to investigate and characterize the cells of origin of thyroid and mammary cancers and the effects of radiation on them (C185). To study these progenitor cells in vivo it is necessary to have a system by which their concentrations, total numbers and responses to radiation and other factors can be measured. It is a truism that not all cells in a tissue are equally sensitive to neoplastic initiation. They reasoned that the progenitor cells are most likely members of that subpopulation that is necessary to maintenance of normal tissue cell numbers and to repair and replacement after tissue damage. They further reasoned that such cells would likely be responsive to specific mitogenic stimulation by hormones. On the basis of these considerations, they developed quantitative rat thyroid and mammary epithelial cell transplantation systems.

  2. Radiogenic neoplasia in thyroid and mammary clonogens. Final progress report, 1 January 1987--31 December 1997

    International Nuclear Information System (INIS)

    Clifton, K.H.

    1998-01-01

    The induction of cancer by ionizing radiation is a matter of great practical importance to the nuclear industry, to national defense, to radiological medicine and to the general public. It is increasingly apparent that carcinogenesis is a leading dose-limiting effect of radiation exposure. The thyroid and mammary glands are among the most sensitive human tissues to radiogenic initiation of cancer, and there is a profoundly higher risk of neoplastic initiation in these glands among individuals irradiated before or during puberty than among those exposed in later life. The authors developed unique quantitative experimental models to investigate and characterize the cells of origin of thyroid and mammary cancers and the effects of radiation on them (C185). To study these progenitor cells in vivo it is necessary to have a system by which their concentrations, total numbers and responses to radiation and other factors can be measured. It is a truism that not all cells in a tissue are equally sensitive to neoplastic initiation. They reasoned that the progenitor cells are most likely members of that subpopulation that is necessary to maintenance of normal tissue cell numbers and to repair and replacement after tissue damage. They further reasoned that such cells would likely be responsive to specific mitogenic stimulation by hormones. On the basis of these considerations, they developed quantitative rat thyroid and mammary epithelial cell transplantation systems

  3. Number and location of mouse mammary tumor virus proviral DNA in mouse DNA of normal tissue and of mammary tumors.

    Science.gov (United States)

    Groner, B; Hynes, N E

    1980-01-01

    The Southern DNA filter transfer technique was used to characterize the genomic location of the mouse mammary tumor proviral DNA in different inbred strains of mice. Two of the strains (C3H and CBA) arose from a cross of a Bagg albino (BALB/c) mouse and a DBA mouse. The mouse mammary tumor virus-containing restriction enzyme DNA fragments of these strains had similar patterns, suggesting that the proviruses of these mice are in similar genomic locations. Conversely, the pattern arising from the DNA of the GR mouse, a strain genetically unrelated to the others, appeared different, suggesting that its mouse mammary tumor proviruses are located in different genomic sites. The structure of another gene, that coding for beta-globin, was also compared. The mice strains which we studied can be categorized into two classes, expressing either one or two beta-globin proteins. The macroenvironment of the beta-globin gene appeared similar among the mice strains belonging to one genetic class. Female mice of the C3H strain exogenously transmit mouse mammary tumor virus via the milk, and their offspring have a high incidence of mammary tumor occurrence. DNA isolated from individual mammary tumors taken from C3H mice or from BALB/c mice foster nursed on C3H mothers was analyzed by the DNA filter transfer technique. Additional mouse mammary tumor virus-containing fragments were found in the DNA isolated from each mammary tumor. These proviral sequences were integrated into different genomic sites in each tumor. Images PMID:6245257

  4. Sterol regulatory element-binding proteins are regulators of the sodium/iodide symporter in mammary epithelial cells.

    Science.gov (United States)

    Wen, G; Pachner, L I; Gessner, D K; Eder, K; Ringseis, R

    2016-11-01

    The sodium/iodide symporter (NIS), which is essential for iodide concentration in the thyroid, is reported to be transcriptionally regulated by sterol regulatory element-binding proteins (SREBP) in rat FRTL-5 thyrocytes. The SREBP are strongly activated after parturition and throughout lactation in the mammary gland of cattle and are important for mammary epithelial cell synthesis of milk lipids. In this study, we tested the hypothesis that the NIS gene is regulated also by SREBP in mammary epithelial cells, in which NIS is functionally expressed during lactation. Regulation of NIS expression and iodide uptake was investigated by means of inhibition, silencing, and overexpression of SREBP and by reporter gene and DNA-binding assays. As a mammary epithelial cell model, the human MCF-7 cell line, a breast adenocarcinoma cell line, which shows inducible expression of NIS by all-trans retinoic acid (ATRA), and unlike bovine mammary epithelial cells, is widely used to investigate the regulation of mammary gland NIS and NIS-specific iodide uptake, was used. Inhibition of SREBP maturation by treatment with 25-hydroxycholesterol (5 µM) for 48h reduced ATRA (1 µM)-induced mRNA concentration of NIS and iodide uptake in MCF-7 cells by approximately 20%. Knockdown of SREBP-1c and SREBP-2 by RNA interference decreased the mRNA and protein concentration of NIS by 30 to 50% 48h after initiating knockdown, whereas overexpression of nuclear SREBP (nSREBP)-1c and nSREBP-2 increased the expression of NIS in MCF-7 cells by 45 to 60%, respectively, 48h after initiating overexpression. Reporter gene experiments with varying length of NIS promoter reporter constructs revealed that the NIS 5'-flanking region is activated by nSREBP-1c and nSREBP-2 approximately 1.5- and 4.5-fold, respectively, and activation involves a SREBP-binding motif (SRE) at -38 relative to the transcription start site of the NIS gene. Gel shift assays using oligonucleotides spanning either the wild-type or the

  5. Harderian Gland Tumorigenesis: Low-Dose and LET Response

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Polly Y. [SRI International, Menlo Park, CA (United States). Biosciences Div.; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Cucinotta, Francis A. [Univ. of Nevada, Las Vegas, NV (United States). Dept. of Health Physics and Diagnostic Sciences; Bjornstad, Kathleen A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Bakke, James [SRI International, Menlo Park, CA (United States). Biosciences Div.; Rosen, Chris J. [SRI International, Menlo Park, CA (United States). Biosciences Div.; Du, Nicholas [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Fairchild, David G. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Cacao, Eliedonna [Univ. of Nevada, Las Vegas, NV (United States). Dept. of Health Physics and Diagnostic Sciences; Blakely, Eleanor A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.

    2016-04-19

    Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ~70 keV/μm) and 1,000 MeV/u titanium (LET ~100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the

  6. Lymphatic vessels assessment in feline mammary tumours

    International Nuclear Information System (INIS)

    Sarli, Giuseppe; Sassi, Francesco; Brunetti, Barbara; Rizzo, Antonio; Diracca, Laura; Benazzi, Cinzia

    2007-01-01

    The lymphatic vessels play a crucial role in a variety of human cancers since tumour cell lymphatic invasion significantly influences prognosis. It is not known if pre-existing lymphatics are enough for tumour dissemination or de novo development is necessary. VEGFR-3 is an angiogenetic mediator for both lymphatic and blood vessels during embryonic development, and only for lymphatics after birth. VEGF is a mediator of both vasculogenesis and angiogenesis, regulates the growth of lymphatics in various experimental models, and is produced in many solid tumours. CD44 mediates hyaluronic acid (HA)-dependent cell adhesion: besides promoting invasion, this interaction also supports neoangiogenesis that indirectly stimulates tumour cell proliferation. The expression of VEGF-C (Vascular Endothelial Growth Factor – C), its receptor VEGFR-3 and CD44, were studied on feline mammary samples to assess the importance of lymphangiogenesis and lymphangiotrophism in neoplasia. Samples were taken from six normal mammary glands (NMG), ten benign (BT) and 32 malignant (MT) tumours. Immunohistochemical laminin/VEGFR-3 double stain, VEGF-C and CD44 stains were applied to 4 μm-thick sections, and their expression evaluated in intratumoral/extratumoral and intramammary/extramammary fields. All groups revealed a higher number of lymphatics in the extratumoral/extramammary areas. VEGF-C expression in the epithelium paralleled the number of positive vessels in the NMG, BT and MT, whereas VEGF-C higher expression was noted in the intratumoral fields only in infiltrating MT. CD44 score was lower in extratumoral than intratumoral fields in tumours and showed a significant increase in extramammary/extratumoral fields from NMG to MT. Pearson test showed a significant and inversely proportional correlation between CD44 expression and the number of lymphatic vessels with VEGFR-3 in malignant infiltrating tumours. The number of both VEGFR-3 positive and negative lymphatics in the extratumoral

  7. The Cytoplasmic Domain of MUC1 Induces Hyperplasia in the Mammary Gland and Correlates with Nuclear Accumulation of β-Catenin

    Science.gov (United States)

    Li, Yuan; Yi, Haiying; Yao, Yixin; Liao, Xiaodong; Xie, Yiqun; Yang, Jie; Yan, Zheng; Wang, Long; Lu, Shunyuan; Kuang, Ying; Gu, Mingmin; Fei, Jian; Wang, Zhugang; Huang, Lei

    2011-01-01

    MUC1 is an oncoprotein that is overexpressed in up to 90% of breast carcinomas. A previous in vitro study by our group demonstrated that the cytoplasmic domain of MUC1 (MUC1-CD), the minimal functional unit of MUC1, contributes to the malignant phenotype in cells by binding directly to β-catenin and protecting β-catenin from GSK3β-induced degradation. To understand the in vivo role of MUC1-CD in breast development, we generated a MUC1-CD transgenic mouse model under the control of the MMTV promoter in a C57BL/6J background, which is more resistant to breast tumor. We show that the expression of MUC1-CD in luminal epithelial cells of the mammary gland induced a hyperplasia phenotype characterized by the development of hyper-branching and extensive lobuloalveoli in transgenic mice. In addition to this hyperplasia, there was a marked increase in cellular proliferation in the mouse mammary gland. We further show that MUC1-CD induces nuclear localization of β-catenin, which is associated with a significant increase of β-catenin activity, as shown by the elevated expression of cyclin D1 and c-Myc in MMTV-MUC1-CD mice. Consistent with this finding, we observed that overexpression of MUC1-C is associated with β-catenin nuclear localization in tumor tissues and increased expression of Cyclin D1 and c-Myc in breast carcinoma specimens. Collectively, our data indicate a critical role for MUC1-CD in the development of mammary gland preneoplasia and tumorigenesis, suggesting MUC1-CD as a potential target for the diagnosis and chemoprevention of human breast cancer. PMID:21533058

  8. The cytoplasmic domain of MUC1 induces hyperplasia in the mammary gland and correlates with nuclear accumulation of β-catenin.

    Directory of Open Access Journals (Sweden)

    Yuan Li

    Full Text Available MUC1 is an oncoprotein that is overexpressed in up to 90% of breast carcinomas. A previous in vitro study by our group demonstrated that the cytoplasmic domain of MUC1 (MUC1-CD, the minimal functional unit of MUC1, contributes to the malignant phenotype in cells by binding directly to β-catenin and protecting β-catenin from GSK3β-induced degradation. To understand the in vivo role of MUC1-CD in breast development, we generated a MUC1-CD transgenic mouse model under the control of the MMTV promoter in a C57BL/6J background, which is more resistant to breast tumor. We show that the expression of MUC1-CD in luminal epithelial cells of the mammary gland induced a hyperplasia phenotype characterized by the development of hyper-branching and extensive lobuloalveoli in transgenic mice. In addition to this hyperplasia, there was a marked increase in cellular proliferation in the mouse mammary gland. We further show that MUC1-CD induces nuclear localization of β-catenin, which is associated with a significant increase of β-catenin activity, as shown by the elevated expression of cyclin D1 and c-Myc in MMTV-MUC1-CD mice. Consistent with this finding, we observed that overexpression of MUC1-C is associated with β-catenin nuclear localization in tumor tissues and increased expression of Cyclin D1 and c-Myc in breast carcinoma specimens. Collectively, our data indicate a critical role for MUC1-CD in the development of mammary gland preneoplasia and tumorigenesis, suggesting MUC1-CD as a potential target for the diagnosis and chemoprevention of human breast cancer.

  9. Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers.

    Science.gov (United States)

    Cleary, Allison S; Leonard, Travis L; Gestl, Shelley A; Gunther, Edward J

    2014-04-03

    Cancer genome sequencing studies indicate that a single breast cancer typically harbours multiple genetically distinct subclones. As carcinogenesis involves a breakdown in the cell-cell cooperation that normally maintains epithelial tissue architecture, individual subclones within a malignant microenvironment are commonly depicted as self-interested competitors. Alternatively, breast cancer subclones might interact cooperatively to gain a selective growth advantage in some cases. Although interclonal cooperation has been shown to drive tumorigenesis in fruitfly models, definitive evidence for functional cooperation between epithelial tumour cell subclones in mammals is lacking. Here we use mouse models of breast cancer to show that interclonal cooperation can be essential for tumour maintenance. Aberrant expression of the secreted signalling molecule Wnt1 generates mixed-lineage mammary tumours composed of basal and luminal tumour cell subtypes, which purportedly derive from a bipotent malignant progenitor cell residing atop a tumour cell hierarchy. Using somatic Hras mutations as clonal markers, we show that some Wnt tumours indeed conform to a hierarchical configuration, but that others unexpectedly harbour genetically distinct basal Hras mutant and luminal Hras wild-type subclones. Both subclones are required for efficient tumour propagation, which strictly depends on luminally produced Wnt1. When biclonal tumours were challenged with Wnt withdrawal to simulate targeted therapy, analysis of tumour regression and relapse revealed that basal subclones recruit heterologous Wnt-producing cells to restore tumour growth. Alternatively, in the absence of a substitute Wnt source, the original subclones often evolve to rescue Wnt pathway activation and drive relapse, either by restoring cooperation or by switching to a defector strategy. Uncovering similar modes of interclonal cooperation in human cancers may inform efforts aimed at eradicating tumour cell communities.

  10. Apoptosis-promoted tumorigenesis: γ-irradiation-induced thymic lymphomagenesis requires Puma-driven leukocyte death

    OpenAIRE

    Michalak, Ewa M.; Vandenberg, Cassandra J.; Delbridge, Alex R.D.; Wu, Li; Scott, Clare L.; Adams, Jerry M.; Strasser, Andreas

    2010-01-01

    Although tumor development requires impaired apoptosis, we describe a novel paradigm of apoptosis-dependent tumorigenesis. Because DNA damage triggers apoptosis through p53-mediated induction of BH3-only proteins Puma and Noxa, we explored their roles in γ-radiation-induced thymic lymphomagenesis. Surprisingly, whereas Noxa loss accelerated it, Puma loss ablated tumorigenesis. Tumor suppression by Puma deficiency reflected its protection of leukocytes from γ-irradiation-induced death, because...

  11. Intricacies of hedgehog signaling pathways: A perspective in tumorigenesis

    International Nuclear Information System (INIS)

    Kar, Swayamsiddha; Deb, Moonmoon; Sengupta, Dipta; Shilpi, Arunima; Bhutia, Sujit Kumar; Patra, Samir Kumar

    2012-01-01

    The hedgehog (HH) signaling pathway is a crucial negotiator of developmental proceedings in the embryo governing a diverse array of processes including cell proliferation, differentiation, and tissue patterning. The overall activity of the pathway is significantly curtailed after embryogenesis as well as in adults, yet it retains many of its functional capacities. However, aberration in HH signaling mediates the initiation, proliferation and continued sustenance of malignancy in different tissues to varying degrees through different mechanisms. In this review, we provide an overview of the role of constitutively active aberrant HH signaling pathway in different types of human cancer and the underlying molecular and genetic mechanisms that drive tumorigenesis in that particular tissue. An insight into the various modes of anomalous HH signaling in different organs will provide a comprehensive knowledge of the pathway in these tissues and open a window for individually tailored, tissue-specific therapeutic interventions. The synergistic cross talking of HH pathway with many other regulatory molecules and developmentally inclined signaling pathways may offer many avenues for pharmacological advances. Understanding the molecular basis of abnormal HH signaling in cancer will provide an opportunity to inhibit the deregulated pathway in many aggressive and therapeutically challenging cancers where promising options are not available.

  12. Intricacies of hedgehog signaling pathways: A perspective in tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kar, Swayamsiddha; Deb, Moonmoon; Sengupta, Dipta; Shilpi, Arunima; Bhutia, Sujit Kumar [Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008 (India); Patra, Samir Kumar, E-mail: samirp@nitrkl.ac.in [Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela, Odisha 769008 (India)

    2012-10-01

    The hedgehog (HH) signaling pathway is a crucial negotiator of developmental proceedings in the embryo governing a diverse array of processes including cell proliferation, differentiation, and tissue patterning. The overall activity of the pathway is significantly curtailed after embryogenesis as well as in adults, yet it retains many of its functional capacities. However, aberration in HH signaling mediates the initiation, proliferation and continued sustenance of malignancy in different tissues to varying degrees through different mechanisms. In this review, we provide an overview of the role of constitutively active aberrant HH signaling pathway in different types of human cancer and the underlying molecular and genetic mechanisms that drive tumorigenesis in that particular tissue. An insight into the various modes of anomalous HH signaling in different organs will provide a comprehensive knowledge of the pathway in these tissues and open a window for individually tailored, tissue-specific therapeutic interventions. The synergistic cross talking of HH pathway with many other regulatory molecules and developmentally inclined signaling pathways may offer many avenues for pharmacological advances. Understanding the molecular basis of abnormal HH signaling in cancer will provide an opportunity to inhibit the deregulated pathway in many aggressive and therapeutically challenging cancers where promising options are not available.

  13. Molecular genetics of cancer and tumorigenesis: Drosophila models

    Institute of Scientific and Technical Information of China (English)

    Wu-Min Deng

    2011-01-01

    Why do some cells not respond to normal control of cell division and become tumorous? Which signals trigger some tumor cells to migrate and colonize other tissues? What genetic factors are responsible for tumorigenesis and cancer development? What environmental factors play a role in cancer formation and progression? In how many ways can our bodies prevent and restrict the growth of cancerous cells?How can we identify and deliver effective drugs to fight cancer? In the fight against cancer,which kills more people than any other disease,these and other questions have long interested researchers from a diverse range of fields.To answer these questions and to fight cancer more effectively,we must increase our understanding of basic cancer biology.Model organisms,including the fruit fly Drosophila melanogaster,have played instrumental roles in our understanding of this devastating disease and the search for effective cures.Drosophila and its highly effective,easy-touse,and ever-expanding genetic tools have contributed toand enriched our knowledge of cancer and tumor formation tremendously.

  14. Investigating the Role of FIP200 in Mammary Carcinogenesis Using a Transgenic Mouse Model

    National Research Council Canada - National Science Library

    Nagy, Tamas

    2007-01-01

    ...) deletion in mammary-specific polyoma middle-T transgenic mice. We monitored mammary carcinogenesis in positive control (FAKFlox/Flox; MMTV-PyVT) and target (FAKFlox/Flox; MMTV-Cre; MMTV-PyVT) females...

  15. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk. Copyright © 2016 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

  16. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  17. Reactive oxygen species via redox signaling to PI3K/AKT pathway contribute to the malignant growth of 4-hydroxy estradiol-transformed mammary epithelial cells.

    Directory of Open Access Journals (Sweden)

    Victor O Okoh

    Full Text Available The purpose of this study was to investigate the effects of 17-β-estradiol (E2-induced reactive oxygen species (ROS on the induction of mammary tumorigenesis. We found that ROS-induced by repeated exposures to 4-hydroxy-estradiol (4-OH-E2, a predominant catechol metabolite of E2, caused transformation of normal human mammary epithelial MCF-10A cells with malignant growth in nude mice. This was evident from inhibition of estrogen-induced breast tumor formation in the xenograft model by both overexpression of catalase as well as by co-treatment with Ebselen. To understand how 4-OH-E2 induces this malignant phenotype through ROS, we investigated the effects of 4-OH-E2 on redox-sensitive signal transduction pathways. During the malignant transformation process we observed that 4-OH-E2 treatment increased AKT phosphorylation through PI3K activation. The PI3K-mediated phosphorylation of AKT in 4-OH-E2-treated cells was inhibited by ROS modifiers as well as by silencing of AKT expression. RNA interference of AKT markedly inhibited 4-OH-E2-induced in vitro tumor formation. The expression of cell cycle genes, cdc2, PRC1 and PCNA and one of transcription factors that control the expression of these genes - nuclear respiratory factor-1 (NRF-1 was significantly up-regulated during the 4-OH-E2-mediated malignant transformation process. The increased expression of these genes was inhibited by ROS modifiers as well as by silencing of AKT expression. These results indicate that 4-OH-E2-induced cell transformation may be mediated, in part, through redox-sensitive AKT signal transduction pathways by up-regulating the expression of cell cycle genes cdc2, PRC1 and PCNA, and the transcription factor - NRF-1. In summary, our study has demonstrated that: (i 4-OH-E2 is one of the main estrogen metabolites that induce mammary tumorigenesis and (ii ROS-mediated signaling leading to the activation of PI3K/AKT pathway plays an important role in the generation of 4-OH-E2

  18. Modeling mechanical interactions between cancerous mammary acini

    Science.gov (United States)

    Wang, Jeffrey; Liphardt, Jan; Rycroft, Chris

    2015-03-01

    The rules and mechanical forces governing cell motility and interactions with the extracellular matrix of a tissue are often critical for understanding the mechanisms by which breast cancer is able to spread through the breast tissue and eventually metastasize. Ex vivo experimentation has demonstrated the the formation of long collagen fibers through collagen gels between the cancerous mammary acini responsible for milk production, providing a fiber scaffolding along which cancer cells can disorganize. We present a minimal mechanical model that serves as a potential explanation for the formation of these collagen fibers and the resultant motion. Our working hypothesis is that cancerous cells induce this fiber formation by pulling on the gel and taking advantage of the specific mechanical properties of collagen. To model this system, we employ a new Eulerian, fixed grid simulation method to model the collagen as a nonlinear viscoelastic material subject to various forces coupled with a multi-agent model to describe individual cancer cells. We find that these phenomena can be explained two simple ideas: cells pull collagen radially inwards and move towards the tension gradient of the collagen gel, while being exposed to standard adhesive and collision forces.

  19. Impaired CK1 delta activity attenuates SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo.

    Directory of Open Access Journals (Sweden)

    Heidrun Hirner

    Full Text Available Simian virus 40 (SV40 is a powerful tool to study cellular transformation in vitro, as well as tumor development and progression in vivo. Various cellular kinases, among them members of the CK1 family, play an important role in modulating the transforming activity of SV40, including the transforming activity of T-Ag, the major transforming protein of SV40, itself. Here we characterized the effects of mutant CK1δ variants with impaired kinase activity on SV40-induced cell transformation in vitro, and on SV40-induced mammary carcinogenesis in vivo in a transgenic/bi-transgenic mouse model. CK1δ mutants exhibited a reduced kinase activity compared to wtCK1δ in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1δ activity. When stably over-expressed in maximal transformed SV-52 cells, CK1δ mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1δ. To characterize the effects of CK1δ on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1δ under the control of the whey acidic protein (WAP gene promoter, and crossed them with SV40 transgenic WAP-T-antigen (WAP-T mice. Both WAP-T mice as well as WAP-mutCK1δ/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP-mutCK1δ/WAP-T bi-transgenic animals. The reduced CK1δ activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1δ activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP-mutCK1δ/WAP-T tumors was also reflected by a significantly different expression of various genes known to be involved in tumor progression, specifically of those involved in wnt-signaling and DNA

  20. Spontaneously immortalised bovine mammary epithelial cells exhibit a distinct gene expression pattern from the breast cancer cells

    Directory of Open Access Journals (Sweden)

    Li Qianqian

    2010-10-01

    Full Text Available Abstract Background Spontaneous immortalisation of cultured mammary epithelial cells (MECs is an extremely rare event, and the molecular mechanism behind spontaneous immortalisation of MECs is unclear. Here, we report the establishment of a spontaneously immortalised bovine mammary epithelial cell line (BME65Cs and the changes in gene expression associated with BME65Cs cells. Results BME65Cs cells maintain the general characteristics of normal mammary epithelial cells in morphology, karyotype and immunohistochemistry, and are accompanied by the activation of endogenous bTERT (bovine Telomerase Reverse Transcriptase and stabilisation of the telomere. Currently, BME65Cs cells have been passed for more than 220 generations, and these cells exhibit non-malignant transformation. The expression of multiple genes was investigated in BME65Cs cells, senescent BMECs (bovine MECs cells, early passage BMECs cells and MCF-7 cells (a human breast cancer cell line. In comparison with early passage BMECs cells, the expression of senescence-relevant apoptosis-related gene were significantly changed in BME65Cs cells. P16INK4a was downregulated, p53 was low expressed and Bax/Bcl-2 ratio was reversed. Moreover, a slight upregulation of the oncogene c-Myc, along with an undetectable level of breast tumor-related gene Bag-1 and TRPS-1, was observed in BME65Cs cells while these genes are all highly expressed in MCF-7. In addition, DNMT1 is upregulated in BME65Cs. These results suggest that the inhibition of both senescence and mitochondrial apoptosis signalling pathways contribute to the immortality of BME65Cs cells. The expression of p53 and p16INK4a in BME65Cs was altered in the pattern of down-regulation but not "loss", suggesting that this spontaneous immortalization is possibly initiated by other mechanism rather than gene mutation of p53 or p16INK4a. Conclusions Spontaneously immortalised BME65Cs cells maintain many characteristics of normal BMEC cells and

  1. X-ray characteristics of mammary gland changes

    International Nuclear Information System (INIS)

    Popmikhajlova, Kh.

    1977-01-01

    The technical problems on the X-ray presentation of the mammary gland are discussed. The role of film mammography and electroroentgenography for detection of the structural changes in the gland is emphasized. The roentgenomorphologic characteristics of the most common X-ray shadows in the mammary glands, classified by their intensity, form, size, number, structure and arrangement, is presented. For a more rapid and easier characterization of the changes in the different mammary gland diseases, the author developed a practicable work formula. This formula is a decimal fraction, in whose numerator are written the morbidly altered numerically marked quadrants of the right mammary gland and in the dominator - those of the left. This formula is suitable for presentation both of diffuse and of solitary changes in the gland. A brief description of their types is given after the formula. The practical value of the formula for the diagnosis of mammary gland diseases is pointed out. It helps the roent--genologist and the surgeon in the exact localization of the changes and performance of an exact sectorial resection. This, in turn, furnishes better opportunities for the pathologist to gain access exactly to the morbidly altered area, which is of particular importance for detection of intraductal cancer. The convenience of the work formula for a rapid recognition and schematic designation of the findings and in mass prophylactic mammofluorographic screening of women is emphasized. (author)

  2. Quantification of progesterone binding in mammary tissue of pregnant ewes

    International Nuclear Information System (INIS)

    Smith, J.J.; Capuco, A.V.; Akers, R.M.

    1987-01-01

    Progestin-binding sites in mammary tissue from 14 prepartum, multiparous ewes at 50, 80, 115, and 140 d of gestation were demonstrated by the binding of [ 3 H] R5020 (17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione) to ovine mammary cytosol in the presence of sodium molybdate and excess cortisol. Homogenization extracted 89% of total mammary receptors (nuclear) into cytosol. Binding was specific for progestins and was of high affinity. The average dissociation constant for [ 3 H] R5020 specifically bound to receptors extracted into mammary cytosol was 1.9 (+/- .4) x 10 -9 M (n = 14) and did not change significantly over the test period. However, binding capacities (fmol/mg cytosolic protein) differed according to stage of gestation with averages of 125 +/- 53, 149 +/- 26, 656 +/- 216, 57 +/- 22 at 50, 80, 115, and 140 d of pregnancy, respectively. Increased number of progestin-binding sites at 115 d of gestation (whether data are expressed per unit of tissue weight, DNA, or cytosolic protein) suggests that an increase per mammary epithelial cell may be necessary to produce the full lobuloalveolar proliferation observed at this stage of gestation

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    Lifescience Database Archive (English)

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  13. File list: His.Brs.50.AllAg.Mammary_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Brs.50.AllAg.Mammary_cells mm9 Histone Breast Mammary cells SRX187511,SRX187516...,SRX403479,SRX403480 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/His.Brs.50.AllAg.Mammary_cells.bed ...

  14. File list: InP.Brs.10.AllAg.Mammary_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Brs.10.AllAg.Mammary_cells mm9 Input control Breast Mammary cells SRX403481,SRX...187517,SRX187512,SRX403484 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/InP.Brs.10.AllAg.Mammary_cells.bed ...

  15. File list: Oth.Brs.10.AllAg.Mammary_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Brs.10.AllAg.Mammary_cells mm9 TFs and others Breast Mammary cells SRX187508,SR...X187509,SRX187514,SRX403482,SRX403483,SRX852562,SRX852565,SRX187513,SRX852563,SRX852564 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Brs.10.AllAg.Mammary_cells.bed ...

  16. Induction of mouse mammary tumor virus RNA in mammary tumors of BALB/c mice treated with urethane, x-irradiation, and hormones

    International Nuclear Information System (INIS)

    Michalides, R.; van Deemter, L.; Nusse, R.; Hageman, P.

    1979-01-01

    The involvement of mouse mammary tumor virus (MTV) in the development of mammary tumors of nonviral etiology in BALB/c mice was studied by measuring the levels of MTV RNA, MTV DNA, and MTV proteins in spontaneously arising and hormally, chemically, and/or physically induced mammary tumors of BALB/c females. The following results were obtained: (1) spontaneous mammary tumors contained very low levels of MTV RNA; 4 x 10 -6 % of the cytoplasmic RNA was MTV RNA. No MTV proteins could be demonstrated by using sensitive radioimmunoassays for MTV proteins p27 and gp52. (2) Mammary tumors induced by treatments with urethane or x-irradiation alone contained higher levels of MTV RNA; these tumors contained 3- and 19-fold more MTV RNA, respectively, compared with spontaneous mammary tumors. (3) Mammary tumors induced by combined treatment with urethane and x-irradiation expressed high levels of MTV RNA in the mammary tumors; a 1,724-fold increase in MTV RNA content compared with spontaneous mammary tumors was observed. However, very low levels of MTV proteins gp52 and p27 were detected, suggesting some kind of impairment at the translation of MTV RNA. MTV RNA was also induced by this treatment in mammary glands and spleens, but not in the livers of tumor-bearing animals. (4) BALB/c females continuously exposed to prolactin contained high levels of MTV RNA and MTV proteins in stimulated mammary glands and in the hormonally induced mammary tumors. These findings suggest that MTV is not responsible for the maintenance and probably also not for the development of all murine mammary cancers

  17. Modeling invasive lobular breast carcinoma by CRISPR/Cas9-mediated somatic genome editing of the mammary gland.

    Science.gov (United States)

    Annunziato, Stefano; Kas, Sjors M; Nethe, Micha; Yücel, Hatice; Del Bravo, Jessica; Pritchard, Colin; Bin Ali, Rahmen; van Gerwen, Bas; Siteur, Bjørn; Drenth, Anne Paulien; Schut, Eva; van de Ven, Marieke; Boelens, Mirjam C; Klarenbeek, Sjoerd; Huijbers, Ivo J; van Miltenburg, Martine H; Jonkers, Jos

    2016-06-15

    Large-scale sequencing studies are rapidly identifying putative oncogenic mutations in human tumors. However, discrimination between passenger and driver events in tumorigenesis remains challenging and requires in vivo validation studies in reliable animal models of human cancer. In this study, we describe a novel strategy for in vivo validation of candidate tumor suppressors implicated in invasive lobular breast carcinoma (ILC), which is hallmarked by loss of the cell-cell adhesion molecule E-cadherin. We describe an approach to model ILC by intraductal injection of lentiviral vectors encoding Cre recombinase, the CRISPR/Cas9 system, or both in female mice carrying conditional alleles of the Cdh1 gene, encoding for E-cadherin. Using this approach, we were able to target ILC-initiating cells and induce specific gene disruption of Pten by CRISPR/Cas9-mediated somatic gene editing. Whereas intraductal injection of Cas9-encoding lentiviruses induced Cas9-specific immune responses and development of tumors that did not resemble ILC, lentiviral delivery of a Pten targeting single-guide RNA (sgRNA) in mice with mammary gland-specific loss of E-cadherin and expression of Cas9 efficiently induced ILC development. This versatile platform can be used for rapid in vivo testing of putative tumor suppressor genes implicated in ILC, providing new opportunities for modeling invasive lobular breast carcinoma in mice. © 2016 Annunziato et al.; Published by Cold Spring Harbor Laboratory Press.

  18. Isolation and characterization of a new cell line from spontaneous mouse mammary tumour, MBL-6, for in vivo cancer studies

    Directory of Open Access Journals (Sweden)

    Ladan Langroudi

    2017-12-01

    Full Text Available In search for treatments against breast cancer, cell lines are one of the basic resources, particularly as in vitro models. Additionally, animal models of cancer are used as the successive step in therapeutics research. In this regard, human breast cancer cell lines provide fundamental models in vitro. However, in vivo studies require immunodeficient mice, which lack the influence of other in vivo factors such as the native microenvironment and the immune system. There are few standard models to study the pathogenic mechanism at molecular level and cell signaling pathway of breast cancer. In this study, a new mouse breast cancer cell line, MBL-6, was successfully established and characterized from tissues of a spontaneous mammary tumor. The cell line had epithelial morphology, formed adherent monolayer, maintained continuously in vitro and was able to form new tumors when injected subcutaneously in syngeneic mice. The growth pattern and metastasis evaluations revealed a considerable in situ duration before invading distant organs. Real time polymerase chain reaction (PCR analysis showed the expression of ER-, PR- and Her-2 receptors. The chromosome analysis showed numerous chromosomal abnormalities. Aggressive tumorigenecity in tumorigenesis test and the IC50 to cyclophosphamide (CTX, celecoxib (CLX and cisplatin (CPN was also evaluated. The numerous tests performed on the new MBL-6 cell line suggest that it is in good quality and may be used in animal models of breast cancer studies.

  19. Study of the G2/M cell cycle checkpoint in irradiated mammary epithelial cells overexpressing Cul-4A gene

    International Nuclear Information System (INIS)

    Gupta, Anu; Yang, L.-X.; Chen, L.-C.

    2002-01-01

    Purpose: Members of the cullin gene family are known to be involved in cell cycle control. One of the cullin genes, Cul-4A, is amplified and overexpressed in breast cancer cells. This study investigates the effect of Cul-4A overexpression upon G2/M cell cycle checkpoint after DNA damage induced by either ionizing or nonionizing radiation. Methods and Materials: The normal mammary epithelial cell line MCF10A was stably transfected with full-length Cul-4A cDNA. Independent clones of MCF10A cells that overexpress Cul-4A proteins were selected and treated with either 8 Gy of ionizing radiation or 7 J/M 2 of UV radiation. The profile of cell cycle progression and the accumulation of several cell cycle proteins were analyzed. Results: We found that overexpression of Cul-4A in MCF10A cells abrogated the G2/M cell cycle checkpoint in response to DNA damage induced by ionizing irradiation, but not to DNA damage induced by nonionizing radiation. Analysis of cell cycle proteins showed that after ionizing irradiation, p53 accumulated in the mock-transfected MCF10A cells, but not in the Cul-4A transfectants. Conclusion: Our results suggest a role for Cul-4A in tumorigenesis and/or tumor progression, possibly through disruption of cell cycle control

  20. Radioanatomic correlations in the study of the intact mammary gland

    Energy Technology Data Exchange (ETDEWEB)

    Kolganova, I P; Zolotarevskii, V B [Pervyj Moskovskii Meditsinskii Inst. (USSR)

    1981-03-01

    The technique and results of parallel X-ray and morphologic study of mammary gland preparations of 30 women of different age who have died for various reasons, are described. The whole preparation is X-rayed in the native state and after fixation in formalline under the same conditions as in the clinic. The mammary gland preparation is split layer-by-layer with the following roentgenography and the study of histological substrate of all shadow elements. The investigations permit to single out 4 types of shadows on the mammograms conditioned by connecting tissue structures with the elements of glandular tissue. A definite type of mammary gland structure on roentgenograms is characteristic of every age period (child-bearing, preclimacteric, climax).

  1. Mammary blood flow regulation in the nursing rabbit

    International Nuclear Information System (INIS)

    Katz, M.; Creasy, R.K.

    1984-01-01

    Cardiac output and mammary blood flow distribution prior to and after suckling were studied in 10 nursing rabbits by means of radionuclide-labeled microspheres. Suckling was followed by a 5.8% rise in cardiac output and a 20.4% rise in mammary blood flow. Determinations of intraglandular blood flow distribution have shown that there was a 43% increase in blood flow to the glands suckled from as compared to a 22.7% rise to the contralateral untouched glands and a 4.9% rise in the remainder of untouched glands. The conclusion is that a local mechanism may be involved in the regulation of mammary blood flow in the nursing rabbit

  2. Radioanatomic correlations in the study of the intact mammary gland

    International Nuclear Information System (INIS)

    Kolganova, I.P.; Zolotarevskij, V.B.

    1981-01-01

    The technique and results of parallel X-ray and morphologic study of mammary gland preparations of 30 women of different age who have died for various reasons, are described. The whole preparation is X-rayed in the native state and after fixation in formalline under the same conditions as in the clinic. The mammary gland preparation is split layer-by-layer with the following roentgenography and the study of histological substrate of all shadow elements. The investigations permit to single out 4 types of shadows on the mammograms conditioned by connecting tissue structures with the elements of glandular tissue. A definite type of mammary gland structure on roentgenograms is characteristic of every age period (child-bearing, preclimacteric, climax) [ru

  3. Distribution of internal mammary lymphadenopathy in breast carcinoma: CT appraisal

    International Nuclear Information System (INIS)

    Scatarige, J.C.; Fishman, E.K.; Zinreich, E.S.; Almaraz, R.

    1987-01-01

    The authors studied the anatomic distribution of enlarged internal mammary lymph nodes in breast carcinoma by reviewing thoracic CT examinations in 219 women with operable, advanced or recurrent disease. Enlarged internal mammary lymph nodes were observed in 45 patients (20.5%); they were unilateral in 32 and bilateral in 13. Lymphadenopathy was limited to one anterior intercostal space in 43%, two spaces in 26%, and three or more species in 31%. Dominant modal disease was centered at the first anterior intercostal space in 14%, the second space in 60%, and the third space in 26%. Isolated adenopathy in the fourth intercostal space was not observed. The authors' data concur with current surgical practice when internal mammary lymph nodes are sampled. Implications for preoperative imaging strategy are discussed

  4. Irradiation strongly reduces tumorigenesis of human induced pluripotent stem cells

    International Nuclear Information System (INIS)

    Inui, Shoki; Minami, Kazumasa; Ito, Emiko; Imaizumi, Hiromasa; Mori, Seiji; Koizumi, Masahiko; Fukushima, Satsuki; Miyagawa, Shigeru; Sawa, Yoshiki; Matsuura, Nariaki

    2017-01-01

    Induced pluripotent stem (iPS) cells have demonstrated they can undergo self-renewal, attain pluripotency, and differentiate into various types of functional cells. In clinical transplantation of iPS cells, however, a major problem is the prevention of tumorigenesis. We speculated that tumor formation could be inhibited by means of irradiation. Since the main purpose of this study was to explore the prevention of tumor formation in human iPS (hiPS) cells, we tested the effects of irradiation on tumor-associated factors such as radiosensitivity, pluripotency and cell death in hiPS cells. The irradiated hiPS cells showed much higher radiosensitivity, because the survival fraction of hiPS cells irradiated with 2 Gy was < 10%, and there was no change of pluripotency. Irradiation with 2 and 4 Gy caused substantial cell death, which was mostly the result of apoptosis. Irradiation with 2 Gy was detrimental enough to cause loss of proliferation capability and trigger substantial cell death in vitro. The hiPS cells irradiated with 2 Gy were injected into NOG mice (NOD/Shi-scid, IL-2 Rγnull) for the analysis of tumor formation. The group of mice into which hiPS cells irradiated with 2 Gy was transplanted showed significant suppression of tumor formation in comparison with that of the group into which non-irradiated hiPS cells were transplanted. It can be presumed that this diminished rate of tumor formation was due to loss of proliferation and cell death caused by irradiation. Our findings suggest that tumor formation following cell therapy or organ transplantation induced by hiPS cells may be prevented by irradiation.

  5. Conserved mechanisms of tumorigenesis in the Drosophila adult midgut.

    Directory of Open Access Journals (Sweden)

    Òscar Martorell

    Full Text Available Whereas the series of genetic events leading to colorectal cancer (CRC have been well established, the precise functions that these alterations play in tumor progression and how they disrupt intestinal homeostasis remain poorly characterized. Activation of the Wnt/Wg signaling pathway by a mutation in the gene APC is the most common trigger for CRC, inducing benign lesions that progress to carcinomas due to the accumulation of other genetic alterations. Among those, Ras mutations drive tumour progression in CRC, as well as in most epithelial cancers. As mammalian and Drosophila's intestines share many similarities, we decided to explore the alterations induced in the Drosophila midgut by the combined activation of the Wnt signaling pathway with gain of function of Ras signaling in the intestinal stem cells. Here we show that compound Apc-Ras clones, but not clones bearing the individual mutations, expand as aggressive intestinal tumor-like outgrowths. These lesions reproduce many of the human CRC hallmarks such as increased proliferation, blockade of cell differentiation and cell polarity and disrupted organ architecture. This process is followed by expression of tumoral markers present in human lesions. Finally, a metabolic behavioral assay shows that these flies suffer a progressive deterioration in intestinal homeostasis, providing a simple readout that could be used in screens for tumor modifiers or therapeutic compounds. Taken together, our results illustrate the conservation of the mechanisms of CRC tumorigenesis in Drosophila, providing an excellent model system to unravel the events that, upon mutation in Apc and Ras, lead to CRC initiation and progression.

  6. Implication of Heat Shock Factors in Tumorigenesis: Therapeutical Potential

    International Nuclear Information System (INIS)

    Thonel, Aurelie de; Mezger, Valerie; Garrido, Carmen

    2011-01-01

    Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stresses and in pathological conditions. Increasing evidence indicates that this ancient transcriptional protective program acts genome-widely and performs unexpected functions in the absence of experimentally defined stress. Indeed, HSFs are able to re-shape cellular pathways controlling longevity, growth, metabolism and development. The most well studied HSF, HSF1, has been found at elevated levels in tumors with high metastatic potential and is associated with poor prognosis. This is partly explained by the above-mentioned cytoprotective (HSP-dependent) function that may enable cancer cells to adapt to the initial oncogenic stress and to support malignant transformation. Nevertheless, HSF1 operates as major multifaceted enhancers of tumorigenesis through, not only the induction of classical heat shock genes, but also of “non-classical” targets. Indeed, in cancer cells, HSF1 regulates genes involved in core cellular functions including proliferation, survival, migration, protein synthesis, signal transduction, and glucose metabolism, making HSF1 a very attractive target in cancer therapy. In this review, we describe the different physiological roles of HSFs as well as the recent discoveries in term of non-cogenic potential of these HSFs, more specifically associated to the activation of “non-classical” HSF target genes. We also present an update on the compounds with potent HSF1-modulating activity of potential interest as anti-cancer therapeutic agents

  7. Molecular mechanisms of thyroid tumorigenesis; Molekulare Mechanismen der Schilddruesentumorgenese

    Energy Technology Data Exchange (ETDEWEB)

    Krause, K.; Fuehrer, D. [Universitaetsklinikum Leipzig (Germany). Abt. fuer Endokrinolgoie, Diabetologie und Nephrologie

    2008-09-15

    Thyroid nodules are the most frequent endocrine disorder and occur in approximately 30% of the German population. Thyroid nodular disease constitutes a very heterogeneous entity. A striking diversity of possible functional and morphological features of a thyroid tumour derived from the same thyroid ancestor cell, is a hallmark of thyroid tumorigenesis and is due to specific genetic alterations. Defects in known candidate genes can be found in up to 70% of differentiated thyroid carcinomas and determine the respective cancer phenotype. Papillary thyroid cancers (PTC) harbour BRAF (or much less frequently RAS) mutations in sporadically occurring tumours, while radiation-induced PTC display chromosomal rearrangements such as RET, TRK, APR9 / BRAF. These genetic events results in constitutive MAPKinase activation. Follicular thyroid cancers (FTC) harbour RAS mutations or PAX8/ PPAR{gamma} rearrangements, both of which, however have also been identified in follicular adenoma. In addition, recent studies show, that activation of PI3K/AKT signalling occurs with high frequency in follicular thyroid tumours. Undifferentiated (anaplastic) thyroid cancers (ATC) display genetic features of FTC or PTC, in addition to aberant activation of multiple tyrosinkinase pathways (overexpression or mutations in PI3K and MAPK pathways). This underscores the concept of a sequential evolution of ATC from differentiated thyroid cancer, a process widely conceived to be triggered by p53 inactivation. In contrast, the molecular pathogenesis of benign thyroid tumours, in particular cold thyroid nodules is less known, except for toxic thyroid nodules, which arise from constitutive activation of cAMP signalling, predominantly through TSHR mutations. (orig.)

  8. Conserved mechanisms of tumorigenesis in the Drosophila adult midgut.

    Science.gov (United States)

    Martorell, Òscar; Merlos-Suárez, Anna; Campbell, Kyra; Barriga, Francisco M; Christov, Christo P; Miguel-Aliaga, Irene; Batlle, Eduard; Casanova, Jordi; Casali, Andreu

    2014-01-01

    Whereas the series of genetic events leading to colorectal cancer (CRC) have been well established, the precise functions that these alterations play in tumor progression and how they disrupt intestinal homeostasis remain poorly characterized. Activation of the Wnt/Wg signaling pathway by a mutation in the gene APC is the most common trigger for CRC, inducing benign lesions that progress to carcinomas due to the accumulation of other genetic alterations. Among those, Ras mutations drive tumour progression in CRC, as well as in most epithelial cancers. As mammalian and Drosophila's intestines share many similarities, we decided to explore the alterations induced in the Drosophila midgut by the combined activation of the Wnt signaling pathway with gain of function of Ras signaling in the intestinal stem cells. Here we show that compound Apc-Ras clones, but not clones bearing the individual mutations, expand as aggressive intestinal tumor-like outgrowths. These lesions reproduce many of the human CRC hallmarks such as increased proliferation, blockade of cell differentiation and cell polarity and disrupted organ architecture. This process is followed by expression of tumoral markers present in human lesions. Finally, a metabolic behavioral assay shows that these flies suffer a progressive deterioration in intestinal homeostasis, providing a simple readout that could be used in screens for tumor modifiers or therapeutic compounds. Taken together, our results illustrate the conservation of the mechanisms of CRC tumorigenesis in Drosophila, providing an excellent model system to unravel the events that, upon mutation in Apc and Ras, lead to CRC initiation and progression.

  9. Implication of Heat Shock Factors in Tumorigenesis: Therapeutical Potential

    Energy Technology Data Exchange (ETDEWEB)

    Thonel, Aurelie de [INSERM U866, Dijon (France); Faculty of Medicine and Pharmacy, University of Burgundy, 21033 Dijon (France); Mezger, Valerie, E-mail: valerie.mezger@univ-paris-diderot.fr [CNRS, UMR7216 Epigenetics and Cell Fate, Paris (France); University Paris Diderot, 75013 Paris (France); Garrido, Carmen, E-mail: valerie.mezger@univ-paris-diderot.fr [INSERM U866, Dijon (France); Faculty of Medicine and Pharmacy, University of Burgundy, 21033 Dijon (France); CHU, Dijon BP1542, Dijon (France)

    2011-03-07

    Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stresses and in pathological conditions. Increasing evidence indicates that this ancient transcriptional protective program acts genome-widely and performs unexpected functions in the absence of experimentally defined stress. Indeed, HSFs are able to re-shape cellular pathways controlling longevity, growth, metabolism and development. The most well studied HSF, HSF1, has been found at elevated levels in tumors with high metastatic potential and is associated with poor prognosis. This is partly explained by the above-mentioned cytoprotective (HSP-dependent) function that may enable cancer cells to adapt to the initial oncogenic stress and to support malignant transformation. Nevertheless, HSF1 operates as major multifaceted enhancers of tumorigenesis through, not only the induction of classical heat shock genes, but also of “non-classical” targets. Indeed, in cancer cells, HSF1 regulates genes involved in core cellular functions including proliferation, survival, migration, protein synthesis, signal transduction, and glucose metabolism, making HSF1 a very attractive target in cancer therapy. In this review, we describe the different physiological roles of HSFs as well as the recent discoveries in term of non-cogenic potential of these HSFs, more specifically associated to the activation of “non-classical” HSF target genes. We also present an update on the compounds with potent HSF1-modulating activity of potential interest as anti-cancer therapeutic agents.

  10. The mammary gland in domestic ruminants: a systems biology perspective.

    Science.gov (United States)

    Ferreira, Ana M; Bislev, Stine L; Bendixen, Emøke; Almeida, André M

    2013-12-06

    Milk and dairy products are central elements in the human diet. It is estimated that 108kg of milk per year are consumed per person worldwide. Therefore, dairy production represents a relevant fraction of the economies of many countries, being cattle, sheep, goat, water buffalo, and other ruminants the main species used worldwide. An adequate management of dairy farming cannot be achieved without the knowledge on the biological mechanisms behind lactation in ruminants. Thus, understanding the morphology, development and regulation of the mammary gland in health, disease and production is crucial. Presently, innovative and high-throughput technologies such as genomics, transcriptomics, proteomics and metabolomics allow a much broader and detailed knowledge on such issues. Additionally, the application of a systems biology approach to animal science is vastly growing, as new advances in one field of specialization or animal species lead to new lines of research in other areas or/and are expanded to other species. This article addresses how modern research approaches may help us understand long-known issues in mammary development, lactation biology and dairy production. Dairy production depends upon the knowledge of the morphology and regulation of the mammary gland and lactation. High-throughput technologies allow a much broader and detailed knowledge on the biology of the mammary gland. This paper reviews the major contributions that genomics, transcriptomics, metabolomics and proteomics approaches have provided to understand the regulation of the mammary gland in health, disease and production. In the context of mammary gland "omics"-based research, the integration of results using a Systems Biology Approach is of key importance. © 2013.

  11. Mammary mechanisms for lactoferrin: interactions with IGFBP-3.

    Directory of Open Access Journals (Sweden)

    Baumrucker C.R.

    2000-01-01

    Full Text Available Lactoferrin (Lf is an iron-binding protein found in high concentrations in mammary secretions but synthesized by many tissues. Bovine mammary tissue secretes microg/ml mass of Lf in milk, but during involution and prepartum periods, 20-80 mg per ml concentrations may be observed. While a number of functions have been ascribed to lactoterrin, only the antimicrobial and lymphocyte interactions have compelling experimental evidence of support. We report a new finding that lactoferrin binds to insulin-like growth factor binding protein-3 (IGFBP-3 and not to other mammary secreted IGFBPs (IGFBP-2, -4. and -5. Furthermore, bovine Lf(bLf is found associated with membranes of mammary cells. We demonstrate that bovine Lf competes with IGF for binding to IGFBP-3 with ED50 competition of 3 microg per ml and displacement of 1 mg per ml to monomeric bLf. The tetrameric form that is favored by high concentrations of Lf and calcium, does not appear to bind IGFBP-3. Both IGFBP-3 and Lf have nuclear localization sequences that are reported to he key components of nuclear localization of proteins. We demonstrate that extracellular IGFBP-3 binds to membrane Lf and that Lf is the key to the entry of IGFBP-3 to mammary cellular nucleus. Additionally, we have shown that the internalization of Lf requires the presence of retinoids that also induces both IGFBP-3 and Lf synthesis in primary cultures of bovine mammary epithelial cells. We hypothesize a new role for Lf in the regulation and integration into the IGF System.

  12. Immunohistochemical detection of estrogen receptors in canine mammary tumors

    Directory of Open Access Journals (Sweden)

    Elena Atanaskova Petrov

    2016-03-01

    Full Text Available Mammary tumors are among the most common neoplasms in intact female dogs.They have a complex morphology, usually affecting middle age and older bitches. Almost 50% of the mammary tumors in dogs are malignant neoplasms. Prognosis is based on several factors: stage, age, tumor size, metastasis, histopathology, ovariectomy status and hormone-receptor activity. Immunohistochemical (IHC measurement has become increasingly an important diagnostic and prognostic parameter, with the development of monoclonal antibodies against nuclear estrogen and progestin receptors. The aim of this study was to detect the presence of ER receptors in malignant canine mammary tumors and to identify their association with the clinical course of the tumor. Mammary tumor samples have been obtained by mastectomy from dogs presented at our clinic. Detailed clinical examination, CBC and basic serum biochemical profile were performed in all patients. Surgery was the only treatment. Histopathological examination and immunohistochemical detection of estrogen α receptors (ERα was performed on 8 formalin-fixed, paraffin-embedded tissue samples, using the PT LINK immunoperoxidase technique. Histopathological examination of the mammary tumor samples (n=11 revealed tubular adenocarcinoma (n=6,54.5% and ductal adenocarcinoma (n=3, 27.3%, one patient with benign adenoma and one with mastitis. Patients with positive ER tumors are alive, without remission, while 3 of the patients that were ER negative died due to lung metastases. According to our results, it can be concluded that the appearance and development of canine mammary tumors is highly connected with ovarian steroid hormones and that immunostaining of the tumors may be used as a good prognostic parameter in these patients.

  13. STAT proteins: from normal control of cellular events to tumorigenesis.

    Science.gov (United States)

    Calò, Valentina; Migliavacca, Manuela; Bazan, Viviana; Macaluso, Marcella; Buscemi, Maria; Gebbia, Nicola; Russo, Antonio

    2003-11-01

    Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors latent in the cytoplasm that participate in normal cellular events, such as differentiation, proliferation, cell survival, apoptosis, and angiogenesis following cytokine, growth factor, and hormone signaling. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulates process. Nevertheless, several constitutively activated STATs have been observed in a wide number of human cancer cell lines and primary tumors, including blood malignancies and solid neoplasias. STATs can be divided into two groups according to their specific functions. One is made up of STAT2, STAT4, and STAT6, which are activated by a small number of cytokines and play a distinct role in the development of T-cells and in IFNgamma signaling. The other group includes STAT1, STAT3, and STAT5, activated in different tissues by means of a series of ligands and involved in IFN signaling, development of the mammary gland, response to GH, and embriogenesis. This latter group of STATS plays an important role in controlling cell-cycle progression and apoptosis and thus contributes to oncogenesis. Although an increased expression of STAT1 has been observed in many human neoplasias, this molecule can be considered a potential tumor suppressor, since it plays an important role in growth arrest and in promoting apoptosis. On the other hand, STAT3 and 5 are considered as oncogenes, since they bring about the activation of cyclin D1, c-Myc, and bcl-xl expression, and are involved in promoting cell-cycle progression, cellular transformation, and in preventing apoptosis.

  14. Proliferation of human mammary cancer cells exposed to 27-hydroxycholesterol

    OpenAIRE

    CRUZ, PAMELA; TORRES, CRISTIAN; RAMÍREZ, MARÍA EUGENIA; EPUÑÁN, MARÍA JOSÉ; VALLADARES, LUIS EMILIO; SIERRALTA, WALTER DANIEL

    2010-01-01

    The aim of the present study was to identify the possible mechanisms by which certain estradiol receptor (ER)-positive mammary tumor cells remain resistant to treatment with anti-estrogens or inhibitors of local estradiol (E2) production. To this end, we compared the proliferative effects on mammary cancer cells of the novel selective ER modulator 27-hydroxycholesterol (27OHC) to those of E2, and evaluated their inhibition by ICI 182,780 (ICI). Analysis of the effects on the cell cycle of 27O...

  15. Large mammary hamartoma with focal invasive ductal carcinoma

    Directory of Open Access Journals (Sweden)

    Pervatikar Suneet

    2009-04-01

    Full Text Available Mammary hamartomas are uncommon benign lesions rarely associated with malignancy. We report a case of a 25-year-old female patient presenting with a lump in the left breast. Fine needle aspiration cytology showed features of invasive ductal carcinoma along with normal benign glands that were mistaken for normal breast tissue. However, the mastectomy specimen revealed the malignant mass within a larger hamartomatous mass. Mammary hamartomas are benign lesions but, on exceedingly rare occasions, they may be involved by incidental, coexisting carcinoma, as illustrated in this case report.

  16. Technical note: Measurement of mammary plasma flow in sows by downstream dilution of mammary vein infused para-aminohippuric acid

    DEFF Research Database (Denmark)

    Larsen, Uffe Krogh; Storm, Adam Christian; Theil, Peter Kappel

    2016-01-01

    catheter was surgically implanted in the femoral artery, and another 2 were inserted in the right cranial mammary vein of 8 second- and third-parity sows on d 76 ± 2 SEM of gestation. On the 3rd and 17th days in milk, arterial and venous blood samples were drawn in hourly intervals from 0.5 h before until...... 6.5 h after feeding. The MPF in the right cranial mammary vein was measured by downstream dilution of infused pAH (3.0 mmol/h). Total MPF-pAH was calculated assuming that the measured flow constituted the flow from 5 out of 14 suckled glands on the basis of the anatomical structure of the mammary...

  17. Reduced HRAS G12V-Driven Tumorigenesis of Cell Lines Expressing KRAS C118S.

    Directory of Open Access Journals (Sweden)

    Lu Huang

    Full Text Available In many different human cancers, one of the HRAS, NRAS, or KRAS genes in the RAS family of small GTPases acquires an oncogenic mutation that renders the encoded protein constitutively GTP-bound and thereby active, which is well established to promote tumorigenesis. In addition to oncogenic mutations, accumulating evidence suggests that the wild-type isoforms may also be activated and contribute to oncogenic RAS-driven tumorigenesis. In this regard, redox-dependent reactions with cysteine 118 (C118 have been found to promote activation of wild-type HRAS and NRAS. We sought to determine if this residue is also important for the activation of wild-type KRAS and promotion of tumorigenesis. Thus, we mutated C118 to serine (C118S in wild-type KRAS to block redox-dependent reactions at this site. We now report that this mutation reduced the level of GTP-bound KRAS and impaired RAS signaling stimulated by the growth factor EGF. With regards to tumorigenesis, we also report that oncogenic HRAS-transformed human cells in which endogenous KRAS was knocked down and replaced with KRASC118S exhibited reduced xenograft tumor growth, as did oncogenic HRAS-transformed KrasC118S/C118S murine cells in which the C118S mutation was knocked into the endogenous Kras gene. Taken together, these data suggest a role for redox-dependent activation of wild-type KRAS through C118 in oncogenic HRAS-driven tumorigenesis.

  18. Heterogeneity of mammary lesions represent molecular differences

    International Nuclear Information System (INIS)

    Namba, Ruria; Gregg, Jeffrey P; Maglione, Jeannie E; Davis, Ryan R; Baron, Colin A; Liu, Stephenie; Carmack, Condie E; Young, Lawrence JT; Borowsky, Alexander D; Cardiff, Robert D

    2006-01-01

    Human breast cancer is a heterogeneous disease, histopathologically, molecularly and phenotypically. The molecular basis of this heterogeneity is not well understood. We have used a mouse model of DCIS that consists of unique lines of mammary intraepithelial neoplasia (MIN) outgrowths, the premalignant lesion in the mouse that progress to invasive carcinoma, to understand the molecular changes that are characteristic to certain phenotypes. Each MIN-O line has distinguishable morphologies, metastatic potentials and estrogen dependencies. We utilized oligonucleotide expression arrays and high resolution array comparative genomic hybridization (aCGH) to investigate whole genome expression patterns and whole genome aberrations in both the MIN-O and tumor from four different MIN-O lines that each have different phenotypes. From the whole genome analysis at 35 kb resolution, we found that chromosome 1, 2, 10, and 11 were frequently associated with whole chromosome gains in the MIN-Os. In particular, two MIN-O lines had the majority of the chromosome gains. Although we did not find any whole chromosome loss, we identified 3 recurring chromosome losses (2F1-2, 3E4, 17E2) and two chromosome copy number gains on chromosome 11. These interstitial deletions and duplications were verified with a custom made array designed to interrogate the specific regions at approximately 550 bp resolution. We demonstrated that expression and genomic changes are present in the early premalignant lesions and that these molecular profiles can be correlated to phenotype (metastasis and estrogen responsiveness). We also identified expression changes associated with genomic instability. Progression to invasive carcinoma was associated with few additional changes in gene expression and genomic organization. Therefore, in the MIN-O mice, early premalignant lesions have the major molecular and genetic changes required and these changes have important phenotypic significance. In contrast, the changes

  19. Role of Mammary Prolactin in Carcinogenesis

    Science.gov (United States)

    1998-10-01

    lactating rats (167) and dairy kines tested, IL-4 was the most potent inhibitor of myome- cows (174) by bromocriptine did not lower immunoreactive trial...of prolactin in dairy cows during lactogenesis. J Dairy 151. Chapitis J, Riddick DH, Betz LM, Brumsted JR, Gibson M, Prior Sci 70:2241-2253 JC, Gout...factors, insulin (30) and EGF (31) stim- ing the presence of functional postreceptor signaling mech- ulate, whereas transforming growth factor-P

  20. Altered oxidative stress and carbohydrate metabolism in canine mammary tumors

    Directory of Open Access Journals (Sweden)

    K. Jayasri

    2016-12-01

    Full Text Available Aim: Mammary tumors are the most prevalent type of neoplasms in canines. Even though cancer induced metabolic alterations are well established, the clinical data describing the metabolic profiles of animal tumors is not available. Hence, our present investigation was carried out with the aim of studying changes in carbohydrate metabolism along with the level of oxidative stress in canine mammary tumors. Materials and Methods: Fresh mammary tumor tissues along with the adjacent healthy tissues were collected from the college surgical ward. The levels of thiobarbituric acid reactive substances (TBARS, glutathione, protein, hexose, hexokinase, glucose-6-phosphatase, fructose-1, 6-bisphosphatase, and glucose-6-phosphate dehydrogenase (G6PD were analyzed in all the tissues. The results were analyzed statistically. Results: More than two-fold increase in TBARS and three-fold increase in glutathione levels were observed in neoplastic tissues. Hexokinase activity and hexose concentration (175% was found to be increased, whereas glucose-6-phosphatase (33%, fructose-1, 6-bisphosphatase (42%, and G6PD (5 fold activities were reduced in tumor mass compared to control. Conclusion: Finally, it was revealed that lipid peroxidation was increased with differentially altered carbohydrate metabolism in canine mammary tumors.

  1. Proliferation of human mammary cancer cells exposed to 27-hydroxycholesterol.

    Science.gov (United States)

    Cruz, Pamela; Torres, Cristian; Ramírez, María Eugenia; Epuñán, María José; Valladares, Luis Emilio; Sierralta, Walter Daniel

    2010-05-01

    The aim of the present study was to identify the possible mechanisms by which certain estradiol receptor (ER)-positive mammary tumor cells remain resistant to treatment with anti-estrogens or inhibitors of local estradiol (E(2)) production. To this end, we compared the proliferative effects on mammary cancer cells of the novel selective ER modulator 27-hydroxycholesterol (27OHC) to those of E(2), and evaluated their inhibition by ICI 182,780 (ICI). Analysis of the effects on the cell cycle of 27OHC and E(2) in the absence or presence of ICI was conducted. In ER-positive mammary tumor cells, we detected the blocking of 27OHC proliferation-stimulatory activity by simvastatin, as well as the inhibition of E(2)-stimulated proliferation by an α-fetoprotein-derived cyclic nonapeptide. The effects reported herein may be extrapolated to infiltrating mammary cancer, where the activity of local macrophages may stimulate tumor growth. We suggest that increased breast cancer growth in obese patients may be related to increased 27OHC circulatory levels.

  2. A mouse model of mammary hyperplasia induced by oral hormone ...

    African Journals Online (AJOL)

    Methods and Materials: To address the mechanism, we developed a mouse model of mammary hyperplasia. We gave mice estradiol valerate tablets and progesterone capsules sequentially for one month by intragastric administration. Results: Mice treated by this method had a series of pathological changes which are ...

  3. Mammary gland chondrosarcoma in a German Shepherd bitch: A ...

    African Journals Online (AJOL)

    Canine mammary tumours are the most common tumours in intact bitches and they constitute about 25% of the neoplasm in this species followed by skin tumours (Benjamin et al.,1999) and their incidence varies from 198 to 622.6 cases per 100,000 dogs per year (Vail and MacEwen,2000). According to Yager et al.(1993) ...

  4. Mammary remodeling in primiparous and multiparous dairy goats during lactation

    DEFF Research Database (Denmark)

    Safayi, Sina; Theil, Peter Kappel; Elbrønd, Vibeke Sødring

    2010-01-01

    Milk production is generally lower but lactation persistency higher in primiparous (PP) than in multiparous (MP) goats. This may be related to differences in development and maintenance of mammary gland function, but the underlying mechanisms are not well understood. The present study aimed to el...

  5. Mammary remodelling and metabolic activity in dairy goats

    DEFF Research Database (Denmark)

    Safayi, Sina

    Milk production is generally lower, but lactation persistency higher in primiparous (PP) than multiparous (MP) ruminants. This may be related to differences in development and maintenance of mammary gland function, but the underlying mechanisms are not well understood. Furthermore, milk productio...

  6. Mammary Analog Secretory Carcinoma of the Nasal Cavity

    DEFF Research Database (Denmark)

    Baneckova, Martina; Agaimy, Abbas; Andreasen, Simon

    2018-01-01

    Secretory carcinoma, originally described as mammary analog secretory carcinoma (MASC), is a low-grade salivary gland tumor characterized by a t(12;15)(p13;q25) translocation, resulting in an ETV6-NTRK3 gene fusion. Most MASCs are localized to the parotid gland and intraoral minor salivary glands...

  7. Mammary fibroadenoma: ductal pattern in pneumo-oncography

    International Nuclear Information System (INIS)

    Pinto Pabon, I.; Garcia Alvarez, A.; Castello Camerlinck, J.

    1988-01-01

    The authors present 25 cases affected by mammary fibroadenoma which underwent pneumo-oncography; in all instances they obtained a characteristic pattern of air distribution, the ductal pattern, which allows fibroadenoma to be reliably diagnosed. No carcinoma demonstrated this type of air pattern. 9 refs.; 3 figs

  8. Detection of Mouse Mammary Tumour Virus in house mice

    DEFF Research Database (Denmark)

    Steffensen, Lise K; Leirs, Herwig; Heiberg, Ann-Charlotte

    The prevalence of human breast cancer (HBC) is affected by several parameters. For the past decades MMTV, Mouse Mammary Tumor Virus, known to cause breast cancer in mice, has been hypothesized to affect the frequency of hormone dependent HBC. Though conclusive evidence has not been produced, still...

  9. Intravital imaging of cancer stem cell plasticity in mammary tumors

    NARCIS (Netherlands)

    Zomer, A.; Ellenbroek, S.I.; Ritsma, L.; Beerling, E.; Vrisekoop, N.; van Rheenen, J.

    2013-01-01

    It is widely debated whether all tumor cells in mammary tumors have the same potential to propagate and maintain tumor growth or whether there is a hierarchical organization. Evidence for the latter theory is mainly based on the ability or failure of transplanted tumor cells to produce detectable

  10. Mammary analogue secretory carcinoma: A rare salivary gland tumour

    African Journals Online (AJOL)

    Salivary gland malignancy is rare, with a global annual incidence of. 3 per 100 000 people.[1,2] A rare salivary gland tumour, mammary analogue secretory carcinoma (MASC), has only recently been described.[3] The few reports and studies concerning MASC have been published in several pathology journals. We report ...

  11. Morphogenesis of Mammary Glands in Buffalo (Bubalus bubalis

    Directory of Open Access Journals (Sweden)

    Amit Challana

    2014-01-01

    Full Text Available The present research was elucidated on the morphogenesis of mammary gland of buffalo during prenatal development. Total of 16 foetuses ranging from 1.2 cm (34 days to 108 cm CVRL (curved crown rump length (317 days were used for study. The study revealed that mammary line was first observed at 1.2 cm CVRL (34 days, mammary hillock at 1.7 cm (37 days, and mammary bud at 2.6 cm CVRL (41 days foetuses. Epidermal cone was found at 6.7 cm CVRL (58 days whereas primary and secondary ducts were observed at 7.4 cm CVRL (62 days and 15 cm CVRL (96 days, respectively. Connective tissue whorls were reported at 18.2 cm CVRL (110 days and internal elastic lamina and muscle layers at 24.1 cm CVRL (129 days. Lobules were observed at 29.3 cm CVRL (140 days, rosette of furstenberg at 39.5 cm CVRL (163 days, and keratin plug at 45.5 cm CVRL (176 days foetus. Primordia of sweat and sebaceous glands around hair follicle were seen at 21.2 cm CVRL (122 days of foetal life. Differentiation of all the skin layers along with cornification was observed at 69 cm (229 days in group III foetuses.

  12. Relationship of histochemically detectable altered hepatocyte foci to hepatic tumorigenesis

    Energy Technology Data Exchange (ETDEWEB)

    Peraino, C.; Staffeldt, E.F.; Carnes, B.A.; Ludeman, V.A.; Blomquist, J.A.; Vesselinovitch, S.D.

    1984-01-01

    A new experimental system was used to examine the stages of chemically induced hepatic neoplasia in the rat. The treatment protocol involved the intraperitoneal injection of a single non-necrogenic dose of carcinogen (N-nitrosodiethylamine (NDEA) or benzo(a)pyrene (BP)) into male and female rats within one day after birth, followed by dietary exposure to promoter (0.05% phenobarbital) from weaning. Rats were killed at intervals, and their livers were examined for tumors and for histochemically detectable foci of altered hepatocytes. The data showed that (1) the new treatment protocol was highly efficient in foci and tumor production; (2) growth rates and incidence levels of foci were directly related to hepatocarcinogenic effectiveness (NDEA > BP), whereas both carcinogens had similar effects on foci phenotypic properties; (3) after their formation, foci at a given level of phenotypic complexity did not become progressively more complex; (4) incidence levels of foci were sex-dependent (females > males), but growth rates of foci were the same for both sexes; (5) growth rates and growth capacities (ranges of possible growth rates) of foci were directly related to phenotypic complexity levels of foci; (6) frequencies and phenotypic complexities of foci were inversely related; the reverse was true for tumors, although 10% of the tumors were relatively simple (three markers or fewer); (7) marker frequency distribution patterns were completely different in foci and in tumors.

  13. Occurrence of mammary tumors in beagls given radium-226

    International Nuclear Information System (INIS)

    Bruenger, F.W.; Lloyd, R.D.; Miller, S.C.; Taylor, G.N.; Angus, W.; Huth, D.A.

    1994-01-01

    A total of 128 primary mammary tumors (66 of them malignant) occurred in 35 female beagles injected with 226 Ra at eight dose levels ranging from 0.2 to 440 kBq/kg body mass as young adults, while a total of 156 mammary tumors (57 of them malignant) were seen in 46 female control beagles not given any radioactivity. Sixty-three of 65 control dogs and 59 of 61 dogs given 226 Ra survived the minimum age for diagnosis of mammary tumors of 3.75 years. Based on the observed age-dependent tumor incidence rates in the controls and on the corresponding number of dog-years at risk, the total number of observed malignant tumors in the radium group was statistically greater than the number of expected malignant tumors (66 observed vs 34 expected, P < 0.005). There was no such difference for the benign tumors. Cox regression analysis indicated no increased risk for the first tumor occurrence in irradiated dogs. Cox regression analysis of the multivariate risk sets showed no significantly increased risk for the occurrence of benign tumors but a statistically higher risk of 1.66 with a confidence interval of 1.15-2.40 for the occurrence of malignant tumors. The increased risk was dependent on dose, but a dependence on the frequency of previous occurrence of mammary tumors could not be confirmed. Censoring ovariectomized dogs at time of surgery decreased the relative risks slightly but did not alter the significance. Exposure to diagnostic X rays with cumulative exposures below 0.2 Gy had no effect on tumor formation. It is unknown whether the increased risk for malignant mammary tumors was due to some initial deposition of radium in sensitive tissue, a possible irradiation of fatty mammary tissue from transient radon → polonium deposition, or a general effect of the overall radium deposition on the immune system of the dogs that lowered their resistance to formation of mammary tumors. 27 refs., 5 figs., 4 tabs

  14. Epimorphin Functions as a Key Morphoregulator for Mammary Epithelial Cells

    Energy Technology Data Exchange (ETDEWEB)

    Hirai, H.; Lochter, A.; Galosy, S.; Koshida, S.; Niwa, S.; Bissell, M.J.

    1997-10-13

    Hepatocyte growth factor (HGF) and EGF have been reported to promote branching morphogenesis of mammary epithelial cells. We now show that it is epimorphin that is primarily responsible for this phenomenon. In vivo, epimorphin was detected in the stromal compartment but not in lumenal epithelial cells of the mammary gland; in culture, however, a subpopulation of mammary epithelial cells produced significant amounts of epimorphin. When epimorphin-expressing epithelial cell clones were cultured in collagen gels they displayed branching morphogenesis in the presence of HGF, EGF, keratinocyte growth factor, or fibroblast growth factor, a process that was inhibited by anti-epimorphin but not anti-HGF antibodies. The branch length, however, was roughly proportional to the ability of the factors to induce growth. Accordingly, epimorphin-negative epithelial cells simply grew in a cluster in response to the growth factors and failed to branch. When recombinant epimorphin was added to these collagen gels, epimorphin-negative cells underwent branching morphogenesis. The mode of action of epimorphin on morphogenesis of the gland, however, was dependent on how it was presented to the mammary cells. If epimorphin was overexpressed in epimorphin-negative epithelial cells under regulation of an inducible promoter or was allowed to coat the surface of each epithelial cell in a nonpolar fashion, the cells formed globular, alveoli-like structures with a large central lumen instead of branching ducts. This process was enhanced also by addition of HGF, EGF, or other growth factors and was inhibited by epimorphin antibodies. These results suggest that epimorphin is the primary morphogen in the mammary gland but that growth factors are necessary to achieve the appropriate cell numbers for the resulting morphogenesis to be visualized.

  15. Internal mammary lymph node management – further direction

    Directory of Open Access Journals (Sweden)

    Vrana D

    2017-02-01

    Full Text Available D Vrana,1,2 J Gatek3,4 1Department of Oncology, 2Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, 3Department of Surgery, Atlas Hospital, 4Faculty of Humanities, Tomas Bata University in Zlín, Zlín, Czech Republic We read the article titled “Internal mammary sentinel lymph node biopsy: abandon or persist?” by Qiu et al with high interest. This was an excellent paper regarding the contemporary management of internal mammary lymph nodes (IMLN in early-stage breast cancer1 and we would like to take this opportunity to comment on this paper.There are several unresolved questions regarding early-stage breast management including axillary staging, clear resection margin, or IMLN.2–4 We have been focusing on the issues of IMLN for almost a decade and just recently published our data regarding IMLN management. We absolutely agree that one has to carefully balance the benefit and potential risks of biopsy or radiotherapy of IMLN.  Authors' reply Peng-Fei Qiu, Yong-Sheng WangBreast Cancer Center, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, People’s Republic of China  We appreciate the letter from Professors Vrana and Gatek regarding our article titled “Internal mammary sentinel lymph node biopsy: abandon or persist?”.1 We have been following their publications regarding internal mammary lymph nodes (IMLN management since the publication of their article titled “Prognostic influence of internal mammary node drainage in patients with early-stage breast cancer” in December 20162 and we share their interest on this topic.  View the original paper by Qiu and colleagues.

  16. Comparative expression pathway analysis of human and canine mammary tumors

    Directory of Open Access Journals (Sweden)

    Marconato Laura

    2009-03-01

    Full Text Available Abstract Background Spontaneous tumors in dog have been demonstrated to share many features with their human counterparts, including relevant molecular targets, histological appearance, genetics, biological behavior and response to conventional treatments. Mammary tumors in dog therefore provide an attractive alternative to more classical mouse models, such as transgenics or xenografts, where the tumour is artificially induced. To assess the extent to which dog tumors represent clinically significant human phenotypes, we performed the first genome-wide comparative analysis of transcriptional changes occurring in mammary tumors of the two species, with particular focus on the molecular pathways involved. Results We analyzed human and dog gene expression data derived from both tumor and normal mammary samples. By analyzing the expression levels of about ten thousand dog/human orthologous genes we observed a significant overlap of genes deregulated in the mammary tumor samples, as compared to their normal counterparts. Pathway analysis of gene expression data revealed a great degree of similarity in the perturbation of many cancer-related pathways, including the 'PI3K/AKT', 'KRAS', 'PTEN', 'WNT-beta catenin' and 'MAPK cascade'. Moreover, we show that the transcriptional relationships between different gene signatures observed in human breast cancer are largely maintained in the canine model, suggesting a close interspecies similarity in the network of cancer signalling circuitries. Conclusion Our data confirm and further strengthen the value of the canine mammary cancer model and open up new perspectives for the evaluation of novel cancer therapeutics and the development of prognostic and diagnostic biomarkers to be used in clinical studies.

  17. Characterization of long noncoding RNA and messenger RNA signatures in melanoma tumorigenesis and metastasis.

    Directory of Open Access Journals (Sweden)

    Siqi Wang

    Full Text Available The incidence of melanoma, the most aggressive and life-threatening form of skin cancer, has significantly risen over recent decades. Therefore, it is essential to identify the mechanisms that underlie melanoma tumorigenesis and metastasis and to explore novel and effective melanoma treatment strategies. Accumulating evidence s uggests that aberrantly expressed long noncoding RNAs (lncRNAs have vital functions in multiple cancers. However, lncRNA functions in melanoma tumorigenesis and metastasis remain unclear. In this study, we investigated lncRNA and messenger RNA (mRNA expression profiles in primary melanomas, metastatic melanomas and normal skin samples from the Gene Expression Omnibus database. We used GSE15605 as the training set (n = 74 and GSE7553 as the validation set (n = 58. In three comparisons (primary melanoma versus normal skin, metastatic melanoma versus normal skin, and metastatic melanoma versus primary melanoma, 178, 295 and 48 lncRNAs and 847, 1758, and 295 mRNAs were aberrantly expressed, respectively. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses to examine the differentially expressed mRNAs, and potential core lncRNAs were predicted by lncRNA-mRNA co-expression networks. Based on our results, 15 lncRNAs and 144 mRNAs were significantly associated with melanoma tumorigenesis and metastasis. A subsequent analysis suggested a critical role for a five-lncRNA signature during melanoma tumorigenesis and metastasis. Low expression of U47924.27 was significantly associated with decreased survival of patients with melanoma. To the best of our knowledge, this study is the first to explore the expression patterns of lncRNAs and mRNAs during melanoma tumorigenesis and metastasis by re-annotating microarray data from the Gene Expression Omnibus (GEO microarray dataset. These findings reveal potential roles for lncRNAs during melanoma tumorigenesis and metastasis and provide a rich candidate

  18. Autocrine-paracrine regulation of the mammary gland.

    Science.gov (United States)

    Weaver, S R; Hernandez, L L

    2016-01-01

    The mammary gland has a remarkable capacity for regulation at a local level, particularly with respect to its main function: milk secretion. Regulation of milk synthesis has significant effects on animal and human health, at the level of both the mother and the neonate. Control by the mammary gland of its essential function, milk synthesis, is an evolutionary necessity and is therefore tightly regulated at a local level. For at least the last 60 yr, researchers have been interested in elucidating the mechanisms underpinning the mammary gland's ability to self-regulate, largely without the influence from systemic hormones or signals. By the 1960s, scientists realized the importance of milk removal in the capacity of the gland to produce milk and that the dynamics of this removal, including emptying of the alveolar spaces and frequency of milking, were controlled locally as opposed to traditional systemic hormonal regulation. Using both in vitro systems and various mammalian species, including goats, marsupials, humans, and dairy cows, it has been demonstrated that the mammary gland is largely self-regulating in its capacity to support the young, which is the evolutionary basis for milk production. Local control occurs at the level of the mammary epithelial cell through pressure and stretching negative-feedback mechanisms, and also in an autocrine fashion through bioactive factors within the milk which act as inhibitors, regulating milk secretion within the alveoli themselves. It is only within the last 20 to 30 yr that potential candidates for these bioactive factors have been examined at a molecular level. Several, including parathyroid hormone-related protein, growth factors (transforming growth factor, insulin-like growth factor, epidermal growth factor), and serotonin, are synthesized within and act upon the gland and possess dynamic receptor activity resulting in diverse effects on growth, calcium homeostasis, and milk composition. This review will focus on the

  19. Heat shock protein expression in canine malignant mammary tumours

    International Nuclear Information System (INIS)

    Romanucci, Mariarita; Marinelli, Alessia; Sarli, Giuseppe; Salda, Leonardo Della

    2006-01-01

    Abnormal levels of Heat Shock Proteins (HSPs) have been observed in many human neoplasms including breast cancer and it has been demonstrated that they have both prognostic and therapeutic implications. In this study, we evaluated immunohistochemical expression of HSPs in normal and neoplastic canine mammary glands and confronted these results with overall survival (OS), in order to understand the role of HSPs in carcinogenesis and to establish their potential prognostic and/or therapeutic value. Immunohistochemical expression of Hsp27, Hsp72, Hsp73 and Hsp90 was evaluated in 3 normal canine mammary glands and 30 malignant mammary tumours (10 in situ carcinomas, 10 invasive carcinomas limited to local structures without identifiable invasion of blood or lymphatic vessels, 10 carcinomas with invasion of blood or lymphatic vessels and/or metastases to regional lymph nodes). A semi-quantitative method was used for the analysis of the results. Widespread constitutive expression of Hsp73 and Hsp90 was detected in normal tissue, Hsp72 appeared to be focally distributed and Hsp27 showed a negative to rare weak immunostaining. In mammary tumours, a significant increase in Hsp27 (P < 0.01), Hsp72 (P < 0.05) and Hsp90 (P < 0.01) expression was observed as well as a significant reduction in Hsp73 (P < 0.01) immunoreactivity compared to normal mammary gland tissue. Hsp27 demonstrated a strong positivity in infiltrating tumour cells and metaplastic squamous elements of invasive groups. High Hsp27 expression also appeared to be significantly correlated to a shorter OS (P = 0.00087). Intense immunolabelling of Hsp72 and Hsp73 was frequently detected in infiltrative or inflammatory tumour areas. Hsp90 expression was high in all tumours and, like Hsp73, it also showed an intense positivity in lymphatic emboli. These results suggest that Hsp27, Hsp72 and Hsp90 are involved in canine mammary gland carcinogenesis. In addition, Hsp27 appears to be implicated in tumour invasiveness and

  20. MicroRNA in Metabolic Re-Programming and Their Role in Tumorigenesis

    Czech Academy of Sciences Publication Activity Database

    Tomasetti, M.; Amati, M.; Santarelli, L.; Neužil, Jiří

    2016-01-01

    Roč. 17, č. 5 (2016), č. článku 754. E-ISSN 1422-0067 Institutional support: RVO:86652036 Keywords : miRNAs * tumorigenesis * miR-126 and cancer-stroma environment * metabolic reprogramming Subject RIV: EB - Genetics ; Molecular Biology

  1. Dietary Factors Modulate Colonic Tumorigenesis Through the Interaction of Gut Microbiota and Host Chloride Channels.

    Science.gov (United States)

    Zhang, Yong; Kang, Chao; Wang, Xiao-Lan; Zhou, Min; Chen, Meng-Ting; Zhu, Xiao-Hui; Liu, Kai; Wang, Bin; Zhang, Qian-Yong; Zhu, Jun-Dong; Mi, Man-Tian

    2018-03-01

    In recent decades, the association among diet, gut microbiota, and the risk of colorectal cancer (CRC) has been established. Gut microbiota and associated metabolites, such as bile acids and butyrate, are now known to play a key role in CRC development. The aim of this study is to identify that the progression to CRC is influenced by cholic acid, sodium butyrate, a high-fat diet, or different dose of dihydromyricetin (DMY) interacted with gut microbiota. An AOM/DSS (azoxymethan/dextran sodium sulfate) model is established to study the gut microbiota compsition before and after tumor formation during colitis-induced tumorigenesis. All above dietary factors profoundly influence the composition of gut microbiota and host colonic tumorigenesis. In addition, mice with DMY-modified initial microbiota display different degrees of chemically induced tumorigenesis. Mechanism analysis reveals that gut microbiota-associated chloride channels participated in colon tumorigenesis. Gut microbiota changes occur in the hyperproliferative stage before tumor formation. Gut microbiota and host chloride channels, both of which are regulated by dietary factors, are associated with CRC development. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Fbxw7 Deletion Accelerates KrasG12D-Driven Pancreatic Tumorigenesis via Yap Accumulation.

    Science.gov (United States)

    Zhang, Qiang; Zhang, Yaqing; Parsels, Joshua D; Lohse, Ines; Lawrence, Theodore S; Pasca di Magliano, Marina; Sun, Yi; Morgan, Meredith A

    2016-11-01

    Pancreatic cancers driven by KRAS mutations require additional mutations for tumor progression. The tumor suppressor FBXW7 is altered in pancreatic cancers, but its contribution to pancreatic tumorigenesis is unknown. To determine potential cooperation between Kras mutation and Fbxw7 inactivation in pancreatic tumorigenesis, we generated P48-Cre;LSL-Kras G12D ;Fbxw7 fl/fl (KFC fl/fl ) compound mice. We found that KFC fl/fl mice displayed accelerated tumorigenesis: all mice succumbed to pancreatic ductal adenocarcinoma (PDA) by 40 days of age, with PDA onset occurring by 2 weeks of age. PDA in KFC fl/fl mice was preceded by earlier onset of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions, and associated with chromosomal instability and the accumulation of Fbxw7 substrates Yes-associated protein (Yap), c-Myc, and Notch. Using KFC fl/fl and FBXW7-deficient human pancreatic cancer cells, we found that Yap silencing attenuated growth promotion by Fbxw7 deletion. Our data demonstrate that Fbxw7 is a potent suppressor of Kras G12D -induced pancreatic tumorigenesis due, at least in part, to negative regulation of Yap. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Naringin, a natural dietary compound, prevents intestinal tumorigenesis in Apc (Min/+) mouse model.

    Science.gov (United States)

    Zhang, Yu-Sheng; Li, Ye; Wang, Yan; Sun, Shi-Yue; Jiang, Tao; Li, Cong; Cui, Shu-Xiang; Qu, Xian-Jun

    2016-05-01

    Naringin is a natural dietary flavonoid compound. We aimed to evaluate the effects of naringin on intestinal tumorigenesis in the adenomatous polyposis coli multiple intestinal neoplasia (Apc (Min/+)) mouse model. Apc (Min/+) mice were given either naringin (150 mg/kg) or vehicle by p.o. gavage daily for 12 consecutive weeks. Mice were killed with ether, and blood samples were collected to assess the concentrations of IL-6 and PGE2. Total intestines were removed, and the number of polyps was examined. Tissue samples of intestinal polyps were subjected to the assays of histopathology, immunohistochemical analysis and Western blotting analysis. Apc (Min/+) mice fed with naringin developed less and smaller polyps in total intestines. Naringin prevented intestinal tumorigenesis without adverse effects. Histopathologic analysis revealed the reduction of dysplastic cells and dysplasia in the adenomatous polyps. The treatments' effects might arise from its anti-proliferation, induction of apoptosis and modulation of GSK-3β and APC/β-catenin signaling pathways. Naringin also exerted its effects on tumorigenesis through anti-chronic inflammation. Naringin prevented intestinal tumorigenesis likely through a collection of activities including anti-proliferation, induction of apoptosis, modulation of GSK-3β and APC/β-catenin pathways and anti-inflammation. Naringin is a potential chemopreventive agent for reducing the risk of colonic cancers.

  4. Single-cell RNA-Seq reveals cell heterogeneity and hierarchy within mouse mammary epithelia.

    Science.gov (United States)

    Sun, Heng; Miao, Zhengqiang; Zhang, Xin; Chan, Un In; Su, Sek Man; Guo, Sen; Wong, Chris Koon Ho; Xu, Xiaoling; Deng, Chu-Xia

    2018-04-17

    The mammary gland is very intricately and well organized into distinct tissues, including epithelia, endothelia, adipocytes, and stromal and immune cells. Many mammary gland diseases, such as breast cancer arise from abnormalities in the mammary epithelium, which is mainly composed of two distinct lineages, the basal and luminal cells. Because of the limitation of traditional transcriptome analysis of bulk mammary cells, the hierarchy and heterogeneity of mammary cells within these two lineages remain unclear. To this end, using single-cell RNA-Seq coupled with FACS analysis and principal component analysis, we determined gene expression profiles of mammary epithelial cells of virgin and pregnant mice. These analyses revealed a much higher heterogeneity among the mammary cells than has been previously reported and enabled cell classification into distinct subgroups according to signature gene markers present in each group. We also identified and verified a rare CDH5+ cell subpopulation within a basal cell lineage as quiescent mammary stem cells (MaSCs). Moreover, using pseudo-temporal analysis, we reconstructed the developmental trajectory of mammary epithelia and uncovered distinct changes in gene expression and in biological functions of mammary cells along the developmental process. In conclusion, our work greatly refines the resolution of the cellular hierarchy in developing mammary tissues. The discovery of CDH5+ cells as MaSCs in these tissues may have implications for our understanding of the initiation, development, and pathogenesis of mammary tumors. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Transcriptomic response of goat mammary epithelial cells to Mycoplasma agalactiae challenge – a preliminary study

    DEFF Research Database (Denmark)

    Ogorevc, Jernej; Mihevc, Sonja Prpar; Hedegaard, Jakob

    2015-01-01

    Mycoplasma agalactiae (Ma) is one of the main aetiological agents of intramammary infections in small ruminants, causing contagious agalactia. To better understand the underlying disease patterns a primary goat mammary epithelial cell (pgMEC) culture was established from the mammary tissue and ch....... Additionally, the results represent comprehensive goat mammary transcriptome information and demonstrate the applicability of the comparative genomics approach for annotation of goat data, using transcriptome information of a closely related species (Bos taurus) as a reference....

  6. A tumoriform lesion of the vulva with features of mammary-type fibrocystic disease.

    Science.gov (United States)

    Konstantinova, Anastasia M; Kacerovska, Denisa; Michal, Michal; Kazakov, Dmitry V

    2013-10-01

    : Fibrocystic disease is a common benign lesion of the breast. Variably sized cysts, apocrine metaplasia, fibrosis, calcification, chronic inflammation, and epithelial hyperplasia are the basic morphological changes seen in mammary fibrocystic disease. We report a rare tumoriform lesion of the vulva with features of fibrocystic disease, which seems to be the first description of this condition in the vulva. The pertinent literature is discussed. The reported lesion further demonstrates the analogy between tumors of anogenital mammary-like glands and mammary neoplasms.

  7. Transcriptomic response of goat mammary epithelial cells to Mycoplasma agalactiae challenge – a preliminary study

    DEFF Research Database (Denmark)

    Ogorevc, Jernej; Mihevc, Sonja Prpar; Hedegaard, Jakob

    2015-01-01

    Mycoplasma agalactiae (Ma) is one of the main aetiological agents of intramammary infections in small ruminants, causing contagious agalactia. To better understand the underlying disease patterns a primary goat mammary epithelial cell (pgMEC) culture was established from the mammary tissue......, steroid metabolism, fatty acid metabolism, apoptosis signalling, transcription regulation, and cell cycle regulation. Based on the results we suggest that mammary epithelial cells in vivo contribute to the immune system by the induced expression of cytokines and other chemotactic agents, activation...

  8. Stromal fibroblasts derived from mammary gland of bovine with mastitis display inflammation-specific changes

    OpenAIRE

    Chen, Qing; He, Guiliang; Zhang, Wenyao; Xu, Tong; Qi, Hongliang; Li, Jing; Zhang, Yong; Gao, Ming-Qing

    2016-01-01

    Fibroblasts are predominant components of mammary stromal cells and play crucial roles in the development and involution of bovine mammary gland; however, whether these cells contribute to mastitis has not been demonstrated. Thus, we have undertaken biological and molecular characterization of inflammation-associated fibroblasts (INFs) extracted from bovine mammary glands with clinical mastitis and normal fibroblasts (NFs) from slaughtered dairy cows because of fractured legs during lactation...

  9. Ocular melanoma and mammary mucinous carcinoma in an African lion.

    Science.gov (United States)

    Cagnini, Didier Q; Salgado, Breno S; Linardi, Juliana L; Grandi, Fabrizio; Rocha, Rafael M; Rocha, Noeme S; Teixeira, Carlos R; Del Piero, Fabio; Sequeira, Julio L

    2012-09-25

    Reports of neoplasms in Panthera species are increasing, but they are still an uncommon cause of disease and death in captive wild felids. The presence of two or more primary tumor in large felids is rarely reported, and there are no documented cases of ocular melanoma and mammary mucinous carcinoma in African lions. An ocular melanoma and a mammary mucinous carcinoma are described in an African lion (Panthera leo). The first tumour was histologically characterized by the presence of epithelioid and fusiform melanocytes, while the latter was composed of mucus-producing cells with an epithelial phenotype that contained periodic acid-Schiff (PAS) and Alcian blue staining mucins. Metastases of both tumor were identified in various organs and indirect immunohistochemistry was used to characterize them. Peribiliary cysts were observed in the liver. This is the first description of these tumor in African lions.

  10. Ocular melanoma and mammary mucinous carcinoma in an African lion

    Directory of Open Access Journals (Sweden)

    Cagnini Didier Q

    2012-09-01

    Full Text Available Abstract Background Reports of neoplasms in Panthera species are increasing, but they are still an uncommon cause of disease and death in captive wild felids. The presence of two or more primary tumor in large felids is rarely reported, and there are no documented cases of ocular melanoma and mammary mucinous carcinoma in African lions. Case presentation An ocular melanoma and a mammary mucinous carcinoma are described in an African lion (Panthera leo. The first tumour was histologically characterized by the presence of epithelioid and fusiform melanocytes, while the latter was composed of mucus-producing cells with an epithelial phenotype that contained periodic acid-Schiff (PAS and Alcian blue staining mucins. Metastases of both tumor were identified in various organs and indirect immunohistochemistry was used to characterize them. Peribiliary cysts were observed in the liver. Conclusions This is the first description of these tumor in African lions.

  11. Modeling and analysis of transport in the mammary glands

    International Nuclear Information System (INIS)

    Quezada, Ana; Vafai, Kambiz

    2014-01-01

    The transport of three toxins moving from the blood stream into the ducts of the mammary glands is analyzed in this work. The model predictions are compared with experimental data from the literature. The utility of the model lies in its potential to improve our understanding of toxin transport as a pre-disposing factor to breast cancer. This work is based on a multi-layer transport model to analyze the toxins present in the breast milk. The breast milk in comparison with other sampling strategies allows us to understand the mass transport of toxins once inside the bloodstream of breastfeeding women. The multi-layer model presented describes the transport of caffeine, DDT and cimetidine. The analysis performed takes into account the unique transport mechanisms for each of the toxins. Our model predicts the movement of toxins and/or drugs within the mammary glands as well as their bioaccumulation in the tissues. (paper)

  12. Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1

    Energy Technology Data Exchange (ETDEWEB)

    Sympson, Carolyn J; Bissell, Mina J; Werb, Zena

    1995-06-01

    An intact basement membrane (BM) is essential for the proper function, differentiation and morphology of many epithelial cells. The disruption or loss of this BM occurs during normal development as well as in the disease state. To examine the importance of BM during mammary gland development in vivo, we generated transgenic mice that inappropriately express autoactivating isoforms of the matrix metalloproteinase stromelysin-1. The mammary glands from these mice are both functionally and morphologically altered throughout development. We have now documented a dramatic incidence of breast tumors in several independent lines of these mice. These data suggest that overexpression of stromelysin-1 and disruption of the BM may be a key step in the multi-step process of breast cancer.

  13. Hormonal homeostasis during radiotherapy in patients with mammary gland cancer

    International Nuclear Information System (INIS)

    Lozins'ka, Yi.M.; Yakimova, T.P.

    1993-01-01

    248 patients with mammary gland cancer (stages 2 and 3) were studied. In 3 stage patients, inhibition of the thyroid gland function, increase of somatotropic hormones (STH) and carcinoembryonic antigen (CEA) concentration, when compared with the respective data in stage 2 patients, were noted. Radiotherapy at stages 2 and 3 of the disease causes various changes of the above-mentioned values. Increase of CEA blood concentration results in inhibition of cellular immune reactions in the tumor stroma and its bed, which influences 5-years' survival of the patients. The authors suggest that at stage 3 mammary gland cancer, homeostasis state occurs in the organism; it differs from that occurring at stage 3 of the disease. Thus, different approaches to treatment at these two stages of the disease are required

  14. Phyllodes malignant mammary tumors:communication of three cases

    International Nuclear Information System (INIS)

    Beschizza, V.; Rosasco, M.; Episcopo, S.; Dorfman, N.; Centurion, D.

    2003-01-01

    Three cases of phyllode malignant mammary tumors were studied in the Anatomo-Pathology Chair of the Montevideo, Uruguay.The discussion covered epidemiology, morphologic staging and biological significance of phyllode tumor within the broader spectrum of libro-epithelial breast tumors.An overview of literature shows that histo-pathological criteria recommended by world Health Organization(WHO) are the ones which determine the behaviour of phyllode mammary tumors, wheter bening, malignant of borderline.Prognostic factors of metastases are those involved in stroma overgrowth, anaplasia high mitotic index and infiltrative edge of tumor.None of the clinical aspects,including tumor size, are significant from the viewpoint of prognosis.Efective treatment is broad extended surgical excision (adequate margins),mastectomy being reserved for large tummors that are borderline, malignant or recurrent

  15. Modeling and analysis of transport in the mammary glands

    Science.gov (United States)

    Quezada, Ana; Vafai, Kambiz

    2014-08-01

    The transport of three toxins moving from the blood stream into the ducts of the mammary glands is analyzed in this work. The model predictions are compared with experimental data from the literature. The utility of the model lies in its potential to improve our understanding of toxin transport as a pre-disposing factor to breast cancer. This work is based on a multi-layer transport model to analyze the toxins present in the breast milk. The breast milk in comparison with other sampling strategies allows us to understand the mass transport of toxins once inside the bloodstream of breastfeeding women. The multi-layer model presented describes the transport of caffeine, DDT and cimetidine. The analysis performed takes into account the unique transport mechanisms for each of the toxins. Our model predicts the movement of toxins and/or drugs within the mammary glands as well as their bioaccumulation in the tissues.

  16. Neuroendocrine carcinoma of the mammary gland in a dog.

    Science.gov (United States)

    Nakahira, R; Michishita, M; Yoshimura, H; Hatakeyama, H; Takahashi, K

    2015-01-01

    A 10-year-old female border collie was presented with a mass (2 cm diameter) in the fifth mammary gland. The mass was located in the subcutis and the cut surface was grey-white in colour. Microscopically, the mass was composed of tumour cells arranged in nests of various sizes separated by delicate fibrovascular stroma. The tumour cells had small, round hypochromatic nuclei and abundant cytoplasm. Metastases were observed in the inguinal lymph node. Immunohistochemically, most tumour cells expressed cytokeratin (CK) 20, chromogranin A, neuron-specific enolase, synaptophysin and oestrogen receptor-β, but not low molecular weight CK (CAM5.2), p63 and insulin. Ultrastructurally, the tumour cells contained a large number of electron-dense granules corresponding to neuroendocrine granules. Based on these findings, this case was diagnosed as a neuroendocrine carcinoma of the mammary gland. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Migrastatin analogues inhibit canine mammary cancer cell migration and invasion.

    Directory of Open Access Journals (Sweden)

    Kinga Majchrzak

    Full Text Available BACKGROUND: Cancer spread to other organs is the main cause of death of oncological patients. Migration of cancer cells from a primary tumour is the crucial step in the complex process of metastasis, therefore blocking this process is currently the main treatment strategy. Metastasis inhibitors derived from natural products, such as, migrastatin, are very promising anticancer agents. Thus, the aim of our study was to investigate the effect of six migrastatin analogues (MGSTA-1 to 6 on migration and invasion of canine mammary adenocarcinoma cell lines isolated from primary tumours and their metastases to the lungs. Canine mammary tumours constitute a valuable tool for studying multiple aspect of human cancer. RESULTS: OUR RESULTS SHOWED THAT TWO OF SIX FULLY SYNTHETIC ANALOGUES OF MIGRASTATIN: MGSTA-5 and MGSTA-6 were potent inhibitors of canine mammary cancer cells migration and invasion. These data were obtained using the wound healing test, as well as trans-well migration and invasion assays. Furthermore, the treatment of cancer cells with the most effective compound (MGSTA-6 disturbed binding between filamentous F-actin and fascin1. Confocal microscopy analyses revealed that treatment with MGSTA-6 increased the presence of unbound fascin1 and reduced co-localization of F-actin and fascin1 in canine cancer cells. Most likely, actin filaments were not cross-linked by fascin1 and did not generate the typical filopodial architecture of actin filaments in response to the activity of MGSTA-6. Thus, administration of MGSTA-6 results in decreased formation of filopodia protrusions and stress fibres in canine mammary cancer cells, causing inhibition of cancer migration and invasion. CONCLUSION: Two synthetic migrastatin analogues (MGSTA-5 and MGSTA-6 were shown to be promising compounds for inhibition of cancer metastasis. They may have beneficial therapeutic effects in cancer therapy in dogs, especially in combination with other anticancer drugs

  18. Cell kinetic parameters of a solid mammary adenocarcinoma

    International Nuclear Information System (INIS)

    Porschen, R.; Feinendegen, L.E.

    1978-01-01

    Several cell kinetic parameters of the mammary adenocarcinoma EO 771 were evaluated by means of tumor volume measurements and of 125 I-UdR. The in-situ measured activity loss rate is disturbed by a slow elimination of labelled necrotic cells and by reutilization of 125 I-UdR. The restrictions of the I-UdR method are mentioned and the measured activity loss rates are compared with calculated volume loss rates. (orig./MG) [de

  19. Comparison of mouse mammary gland imaging techniques and applications: Reflectance confocal microscopy, GFP Imaging, and ultrasound

    International Nuclear Information System (INIS)

    Tilli, Maddalena T; Parrish, Angela R; Cotarla, Ion; Jones, Laundette P; Johnson, Michael D; Furth, Priscilla A

    2008-01-01

    Genetically engineered mouse models of mammary gland cancer enable the in vivo study of molecular mechanisms and signaling during development and cancer pathophysiology. However, traditional whole mount and histological imaging modalities are only applicable to non-viable tissue. We evaluated three techniques that can be quickly applied to living tissue for imaging normal and cancerous mammary gland: reflectance confocal microscopy, green fluorescent protein imaging, and ultrasound imaging. In the current study, reflectance confocal imaging offered the highest resolution and was used to optically section mammary ductal structures in the whole mammary gland. Glands remained viable in mammary gland whole organ culture when 1% acetic acid was used as a contrast agent. Our application of using green fluorescent protein expressing transgenic mice in our study allowed for whole mammary gland ductal structures imaging and enabled straightforward serial imaging of mammary gland ducts in whole organ culture to visualize the growth and differentiation process. Ultrasound imaging showed the lowest resolution. However, ultrasound was able to detect mammary preneoplastic lesions 0.2 mm in size and was used to follow cancer growth with serial imaging in living mice. In conclusion, each technique enabled serial imaging of living mammary tissue and visualization of growth and development, quickly and with minimal tissue preparation. The use of the higher resolution reflectance confocal and green fluorescent protein imaging techniques and lower resolution ultrasound were complementary

  20. Clinicopathologic evaluation of mammary Paget′s disease

    Directory of Open Access Journals (Sweden)

    Meibodi Naser

    2008-01-01

    Full Text Available Mammary and extramammary Paget′s diseases are rare neoplasms of epidermis and mucosal epithelium. Due to their nonspecific and variable clinical view, they have differential diagnosis with eczema, melanoma, Bowen′s disease, etc. To the best of our knowledge, no such study has been performed in Iran regarding the prevalence, clinical aspects, underlying disease and pathological characteristics of these two diseases. In this study, we have evaluated the clinical and histopathological aspects of this disorder. Materials and Methods: In this retrospective study, all Paget′s biopsied samples referred to the Pathology Department of Imam-Reza hospital, Mashhad, since 1984 till 2004 were evaluated. Collected data were analyzed by descriptive statistical methods. Results: Among 98925 specimens, there were 29 cases of Paget′s disease. All cases were married women suffering from mammary Paget. The mean age was 53 ± 11 years. Left and right breast involvement was observed in 17 and 12 cases, all unilateral. The most common clinical view was ulcerated (27% and then erythematosus exudative plaques. More than 50% of patients were symptomatic. Most common symptoms were itching, pain and burning. The exclusive underlying pathological diagnosis was ductal carcinoma (55%. Discussion: In most cases, the clinical view of mammary Paget′s disease was helpful. Unilateral ulcerated plaque was the most common clinical sign. Majority of the accompanying pathology was ductal carcinoma. We had no cases of extramammary Paget′s disease in our study.

  1. Localization of mammary tumors in vivo with 131I-labeled Fab fragments of antibodies against mouse mammary epithelial (MME) antigens

    International Nuclear Information System (INIS)

    Wilbanks, T.; Peterson, J.A.; Miller, S.; Kaufman, L.; Ortendahl, D.; Ceriani, R.L.

    1981-01-01

    The Fab fragments of antibodies against cell-type-specific surface antigens of mouse mammary epithelial cells (MME-antigens) were used to localize mammary tumors successfully. The radioiodine-labeled anti-MME (Fab) was injected into mice carrying simulated mammary metastases, and after 24 hours the amount of label per gram of excised tissue was several times greater in the tumor than in liver, brain, lung, or muscle. Kidney showed considerable accumulation of label but this appeared to be nonspecific. Kinetic studies revealed a rapid elimination of labeled Fab in the urine with only 1% of the injected dose remaining in the entire blood pool after 24 hours. Wit a high-purity germanium camera, mammary tumors were clearly located ty the 131 I-labeled anti-MME (Fab), and normalization to /sup 99m/Tc-pertechnetate distribution in the animal increased the specificity. The density of 131 I-label was fourfold greater over the mammary tumor than over comparable areas of the mouse. No accumulation of 131 I-anti-MME (Fab) was observed in nonmammary tumors nor in mammary tumors when labeled nonspecific Fab was used. An analogous system using an antihuman mammary epithelial antiserum is being developed for localization of breast metastases in humans

  2. Hepato-toxic effect of diuron in albino rats.

    Science.gov (United States)

    Agrawal, R C; Kumar, S

    1999-05-01

    Tumour initiating/promoting effect of diuron, a widely used substituted urea herbicide, was studied in rats using liver tumour model. Chronic exposure to diuron at a dose of 250 mg/kg body wt resulted in high mortality and weight loss in treated animals. The animals which received diuron + HCH treatment showed an increase in size and weight of liver as compared to controls. Liver tumours were not observed in any of the treated group whereas some significant histological changes were seen in diuron treated rat liver. Diuron thus has been found to be hepatotoxic albeit neither tumour initiating nor promoting in rat liver tumorigenesis assay system.

  3. Development of novel murine mammary imaging windows to examine wound healing effects on leukocyte trafficking in mammary tumors with intravital imaging.

    Science.gov (United States)

    Sobolik, Tammy; Su, Ying-Jun; Ashby, Will; Schaffer, David K; Wells, Sam; Wikswo, John P; Zijlstra, Andries; Richmond, Ann

    2016-01-01

    We developed mammary imaging windows (MIWs) to evaluate leukocyte infiltration and cancer cell dissemination in mouse mammary tumors imaged by confocal microscopy. Previous techniques relied on surgical resection of a skin flap to image the tumor microenvironment restricting imaging time to a few hours. Utilization of mammary imaging windows offers extension of intravital imaging of the tumor microenvironment. We have characterized strengths and identified some previously undescribed potential weaknesses of MIW techniques. Through iterative enhancements of a transdermal portal we defined conditions for improved quality and extended confocal imaging time for imaging key cell-cell interactions in the tumor microenvironment.

  4. The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells

    OpenAIRE

    Simian, Marina; Hirai, Yohei; Navre, Marc; Werb, Zena; Lochter, Andre; Bissell, Mina J.

    2001-01-01

    The mammary gland develops its adult form by a process referred to as branching morphogenesis. Many factors have been reported to affect this process. We have used cultured primary mammary epithelial organoids and mammary epithelial cell lines in three-dimensional collagen gels to elucidate which growth factors, matrix metalloproteinases (MMPs) and mammary morphogens interact in branching morphogenesis. Branching stimulated by stromal fibroblasts, epidermal growth factor, fibroblast growth fa...

  5. Ultrasonic characterization of three animal mammary tumors from three-dimensional acoustic tissue models

    Science.gov (United States)

    Mamou, Jonathan M.

    This dissertation investigated how three-dimensional (3D) tissue models can be used to improve ultrasonic tissue characterization (UTC) techniques. Anatomic sites in tissue responsible for ultrasonic scattering are unknown, which limits the potential applications of ultrasound for tumor diagnosis. Accurate 3D models of tumor tissues may help identify the scattering sites. Three mammary tumors were investigated: a rat fibroadenoma, a mouse carcinoma, and a mouse sarcoma. A 3D acoustic tissue model, termed 3D impedance map (3DZM), was carefully constructed from consecutive histologic sections for each tumor. Spectral estimates (scatterer size and acoustic concentration) were obtained from the 3DZMs and compared to the same estimates obtained with ultrasound. Scatterer size estimates for three tumors were found to be similar (within 10%). The 3DZMs were also used to extract tissue-specific scattering models. The scattering models were found to allow clear distinction between the three tumors. This distinction demonstrated that UTC techniques may be helpful for noninvasive clinical tumor diagnosis.

  6. Regulation of gene expression in human mammary epithelium: effect of breast pumping

    Science.gov (United States)

    Little is known of the molecular regulation of human milk production because of limitations in obtaining mammary tissue from lactating women. Our objectives were to evaluate whether RNA isolated from breast milk fat globules (MFGs) could be an alternative to mammary biopsies and to determine whether...

  7. Development of mammary glands of fat sheep submitted to restricted feeding during late pregnancy

    DEFF Research Database (Denmark)

    Nørgaard, Jan Værum; Nielsen, Mette Olaf; Theil, Peter Kappel

    2008-01-01

    Mammary gland development in sheep occurs mainly during puberty and pregnancy. We have investigated the effects of a late gestation feed restriction on mammary gland development in sheep. Five control ewes were slaughtered d -38 from parturition, whereas 10 ewes were fed ad libitum and another 10...

  8. Mammary alveolar epithelial cells convert to brown adipocytes in post-lactating mice

    DEFF Research Database (Denmark)

    Giordano, Antonio; Perugini, Jessica; Kristensen, David Møbjerg

    2017-01-01

    During pregnancy and lactation, subcutaneous white adipocytes in the mouse mammary gland transdifferentiate reversibly to milk-secreting epithelial cells. In this study, we demonstrate by transmission electron microscopy that in the post-lactating mammary gland interscapular multilocular adipocyt...... organ plasticity...

  9. Id-1 is not expressed in the luminal epithelial cells of mammary glands

    International Nuclear Information System (INIS)

    Uehara, Norihisa; Chou, Yu-Chien; Galvez, Jose J; Candia, Paola de; Cardiff, Robert D; Benezra, Robert; Shyamala, Gopalan

    2003-01-01

    The family of inhibitor of differentiation/DNA binding (Id) proteins is known to regulate development in several tissues. One member of this gene family, Id-1, has been implicated in mammary development and carcinogenesis. Mammary glands contain various cell types, among which the luminal epithelial cells are primarily targeted for proliferation, differentiation and carcinogenesis. Therefore, to assess the precise significance of Id-1 in mammary biology and carcinogenesis, we examined its cellular localization in vivo using immunohistochemistry. Extracts of whole mammary glands from wild type and Id-1 null mutant mice, and tissue sections from paraffin-embedded mouse mammary glands from various developmental stages and normal human breast were subjected to immunoblot and immunohistochemical analyses, respectively. In both these procedures, an anti-Id-1 rabbit polyclonal antibody was used for detection of Id-1. In immunoblot analyses, using whole mammary gland extracts, Id-1 was detected. In immunohistochemical analyses, however, Id-1 was not detected in the luminal epithelial cells of mammary glands during any stage of development, but it was detected in vascular endothelial cells. Id-1 is not expressed in the luminal epithelial cells of mammary glands

  10. Mammary stem cells: Novel markers and novel approaches to increase lactation efficiency

    Science.gov (United States)

    Mammary stem cells (MaSC) provide for net growth, renewal and turnover of mammary epithelial cells, and are therefore potential targets for strategies to increase production efficiency. Appropriate regulation of MaSC can potentially benefit milk yield, persistency, dry period management and tissue r...

  11. A Role for PPARβ/δ in Tumor Stroma and Tumorigenesis

    Directory of Open Access Journals (Sweden)

    Rolf Müller

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ is a transcription factor that is activated by endogenous fatty acid ligands and by synthetic agonists. Its role in the regulation of skeletal muscle fatty acid catabolism, glucose homeostasis, and cellular differentiation has been established in multiple studies. On the contrary, a role for PPARβ/δ in tumorigenesis is less clear because there are contradictory reports in the literature. However, the majority of these studies have not examined the role of PPARβ/δ in the tumor stroma. Recent evidence suggests that stromal PPARβ/δ regulates tumor endothelial cell proliferation and promotes differentiation leading to the properly orchestrated events required for tumor blood vessel formation. This review briefly summarizes the significance of these studies that may provide clues to help explain the reported discrepancies in the literature regarding the role of PPARβ/δ in tumorigenesis.

  12. Long noncoding RNA lnc-sox5 modulates CRC tumorigenesis by unbalancing tumor microenvironment.

    Science.gov (United States)

    Wu, Kaiming; Zhao, Zhenxian; Liu, Kuanzhi; Zhang, Jian; Li, Guanghua; Wang, Liang

    2017-07-03

    Long non-coding RNAs (LncRNAs) have been recently regarded as systemic regulators in multiple biologic processes including tumorigenesis. In this study, we observed the expression of lncRNA lnc-sox5 was significantly increased in colorectal cancer (CRC). Despite the CRC cell growth, cell cycle and cell apoptosis was not affected by lnc-sox5 knock-down, lnc-sox5 knock-down suppressed CRC cell migration and invasion. In addition, xenograft animal model suggested that lnc-sox5 knock-down significantly suppressed the CRC tumorigenesis. Our results also showed that the expression of indoleamine 2,3-dioxygenase 1 (IDO1) was significantly reduced by lnc-sox5 knock-down and therefore modulated the infiltration and cytotoxicity of CD3 + CD8 + T cells. Taken together, these results suggested that lnc-sox5 unbalances tumor microenvironment to regulate colorectal cancer progression.

  13. MiR-218 Mediates tumorigenesis and metastasis: Perspectives and implications

    International Nuclear Information System (INIS)

    Lu, Ying-fei; Zhang, Li; Waye, Mary Miu Yee; Fu, Wei-ming; Zhang, Jin-fang

    2015-01-01

    MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. As a highly conserved miRNA across a variety of species, microRNA-218 (miR-218) was found to play pivotal roles in tumorigenesis and progression. A group of evidence has demonstrated that miR-218 acts as a tumor suppressor by targeting many oncogenes related to proliferation, apoptosis and invasion. In this review, we provide a complex overview of miR-218, including its regulatory mechanisms, known functions in cancer and future challenges as a potential therapeutic target in human cancers. - Highlights: • miR-218 is frequently down regulated in multiple cancers. • miR-218 plays pivotal roles in carcinogenesis. • miR-218 mediates proliferation, apoptosis, metastasis, invasion, etc. • miR-218 mediates tumorigenesis and metastasis via multiple pathways

  14. MiR-218 Mediates tumorigenesis and metastasis: Perspectives and implications

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Ying-fei [Institute Guangzhou of Advanced Technology, Chinese Academy of Sciences, Guangzhou (China); Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (China); Zhang, Li [School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (China); Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong (China); Waye, Mary Miu Yee [School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (China); Fu, Wei-ming, E-mail: wm.fu@giat.ac.cn [Institute Guangzhou of Advanced Technology, Chinese Academy of Sciences, Guangzhou (China); School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (China); Zhang, Jin-fang, E-mail: zhangjf06@cuhk.edu.hk [Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong (China); School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong (China); Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen (China)

    2015-05-15

    MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. As a highly conserved miRNA across a variety of species, microRNA-218 (miR-218) was found to play pivotal roles in tumorigenesis and progression. A group of evidence has demonstrated that miR-218 acts as a tumor suppressor by targeting many oncogenes related to proliferation, apoptosis and invasion. In this review, we provide a complex overview of miR-218, including its regulatory mechanisms, known functions in cancer and future challenges as a potential therapeutic target in human cancers. - Highlights: • miR-218 is frequently down regulated in multiple cancers. • miR-218 plays pivotal roles in carcinogenesis. • miR-218 mediates proliferation, apoptosis, metastasis, invasion, etc. • miR-218 mediates tumorigenesis and metastasis via multiple pathways.

  15. Hyaline cartilage formation and tumorigenesis of implanted tissues derived from human induced pluripotent stem cells.

    Science.gov (United States)

    Saito, Taku; Yano, Fumiko; Mori, Daisuke; Kawata, Manabu; Hoshi, Kazuto; Takato, Tsuyoshi; Masaki, Hideki; Otsu, Makoto; Eto, Koji; Nakauchi, Hiromitsu; Chung, Ung-il; Tanaka, Sakae

    2015-01-01

    Induced pluripotent stem cells (iPSCs) are a promising cell source for cartilage regenerative medicine. Meanwhile, the risk of tumorigenesis should be considered in the clinical application of human iPSCs (hiPSCs). Here, we report in vitro chondrogenic differentiation of hiPSCs and maturation of the differentiated hiPSCs through transplantation into mouse knee joints. Three hiPSC clones showed efficient chondrogenic differentiation using an established protocol for human embryonic stem cells. The differentiated hiPSCs formed hyaline cartilage tissues at 8 weeks after transplantation into the articular cartilage of NOD/SCID mouse knee joints. Although tumors were not observed during the 8 weeks after transplantation, an immature teratoma had developed in one mouse at 16 weeks. In conclusion, hiPSCs are a potent cell source for regeneration of hyaline articular cartilage. However, the risk of tumorigenesis should be managed for clinical application in the future.

  16. Stress responsive miR-31 is a major modulator of mouse intestinal stem cells during regeneration and tumorigenesis.

    Science.gov (United States)

    Tian, Yuhua; Ma, Xianghui; Lv, Cong; Sheng, Xiaole; Li, Xiang; Zhao, Ran; Song, Yongli; Andl, Thomas; Plikus, Maksim V; Sun, Jinyue; Ren, Fazheng; Shuai, Jianwei; Lengner, Christopher J; Cui, Wei; Yu, Zhengquan

    2017-09-05

    Intestinal regeneration and tumorigenesis are believed to be driven by intestinal stem cells (ISCs). Elucidating mechanisms underlying ISC activation during regeneration and tumorigenesis can help uncover the underlying principles of intestinal homeostasis and disease including colorectal cancer. Here we show that miR-31 drives ISC proliferation, and protects ISCs against apoptosis, both during homeostasis and regeneration in response to ionizing radiation injury. Furthermore, miR-31 has oncogenic properties, promoting intestinal tumorigenesis. Mechanistically, miR-31 acts to balance input from Wnt, BMP, TGFβ signals to coordinate control of intestinal homeostasis, regeneration and tumorigenesis. We further find that miR-31 is regulated by the STAT3 signaling pathway in response to radiation injury. These findings identify miR-31 as a critical modulator of ISC biology, and a potential therapeutic target for a broad range of intestinal regenerative disorders and cancers.

  17. Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Hiroto Kinoshita

    Full Text Available Interleukin-6 (IL-6 is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial-stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6-positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6(-/- mice with wild-type (WT mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6(-/- mice, compared with WT mice. Impaired tumor development in IL-6(-/- mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3-related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell-conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1 receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis.

  18. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

    DEFF Research Database (Denmark)

    Bartkova, Jirina; Rezaei, Nousin; Liontos, Michalis

    2006-01-01

    Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest...... and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression....

  19. A zebrafish transgenic model of Ewing's sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis.

    Science.gov (United States)

    Leacock, Stefanie W; Basse, Audrey N; Chandler, Garvin L; Kirk, Anne M; Rakheja, Dinesh; Amatruda, James F

    2012-01-01

    Ewing's sarcoma, a malignant bone tumor of children and young adults, is a member of the small-round-blue-cell tumor family. Ewing's sarcoma family tumors (ESFTs), which include peripheral primitive neuroectodermal tumors (PNETs), are characterized by chromosomal translocations that generate fusions between the EWS gene and ETS-family transcription factors, most commonly FLI1. The EWS-FLI1 fusion oncoprotein represents an attractive therapeutic target for treatment of Ewing's sarcoma. The cell of origin of ESFT and the molecular mechanisms by which EWS-FLI1 mediates tumorigenesis remain unknown, and few animal models of Ewing's sarcoma exist. Here, we report the use of zebrafish as a vertebrate model of EWS-FLI1 function and tumorigenesis. Mosaic expression of the human EWS-FLI1 fusion protein in zebrafish caused the development of tumors with histology strongly resembling that of human Ewing's sarcoma. The incidence of tumors increased in a p53 mutant background, suggesting that the p53 pathway suppresses EWS-FLI1-driven tumorigenesis. Gene expression profiling of the zebrafish tumors defined a set of genes that might be regulated by EWS-FLI1, including the zebrafish ortholog of a crucial EWS-FLI1 target gene in humans. Stable zebrafish transgenic lines expressing EWS-FLI1 under the control of the heat-shock promoter exhibit altered embryonic development and defective convergence and extension, suggesting that EWS-FLI1 interacts with conserved developmental pathways. These results indicate that functional targets of EWS-FLI1 that mediate tumorigenesis are conserved from zebrafish to human and provide a novel context in which to study the function of this fusion oncogene.

  20. Internal mammary chain irradiation in breast cancer: State of the art

    International Nuclear Information System (INIS)

    Auberdiac, P.; Cartier, L.; Hau Desbat, N.H.; De Laroche, G.; Magne, N.; Chargari, C.; Zioueche, A.; Melis, A.; Kirova, Y.M.

    2011-01-01

    Radiation therapy has a major role in the management of infiltrative breast cancers. However, there is no consensus for the prophylactic treatment of the internal mammary chain (IMC), with strategies that show strong differences according to centers and physicians. Indications for internal mammary chain radiotherapy are debated, since this treatment significantly increases the dose delivered to the heart and leads to potential technical difficulties. Important prospective data recently suggested that internal mammary chain radiotherapy would not be necessary, even in cases of internal or central tumor locations, or in patients with positive axillary lymph nodes. Although these data warrant confirmation by two other prospective trials, there is evidence that the indications for internal mammary chain radiotherapy should be careful and that high quality techniques should be used for decreasing the dose delivered to the heart. This review of literature presents the state of art on the radiotherapy of internal mammary chain, with special focus on the indications, techniques, and potential toxicity. (authors)

  1. Mechanisms of increased risk of tumorigenesis in Atm and Brca1 double heterozygosity

    International Nuclear Information System (INIS)

    Wang, Jufang; Su, Fengtao; Smilenov, Lubomir B; Zhou, Libin; Hu, Wentao; Ding, Nan; Zhou, Guangming

    2011-01-01

    Both epidemiological and experimental studies suggest that heterozygosity for a single gene is linked with tumorigenesis and heterozygosity for two genes increases the risk of tumor incidence. Our previous work has demonstrated that Atm/Brca1 double heterozygosity leads to higher cell transformation rate than single heterozygosity. However, the underlying mechanisms have not been fully understood yet. In the present study, a series of pathways were investigated to clarify the possible mechanisms of increased risk of tumorigenesis in Atm and Brca1 heterozygosity. Wild type cells, Atm or Brca1 single heterozygous cells, and Atm/Brca1 double heterozygous cells were used to investigate DNA damage and repair, cell cycle, micronuclei, and cell transformation after photon irradiation. Remarkable high transformation frequency was confirmed in Atm/Brca1 double heterozygous cells compared to wild type cells. It was observed that delayed DNA damage recognition, disturbed cell cycle checkpoint, incomplete DNA repair, and increased genomic instability were involved in the biological networks. Haploinsufficiency of either ATM or BRCA1 negatively impacts these pathways. The quantity of critical proteins such as ATM and BRCA1 plays an important role in determination of the fate of cells exposed to ionizing radiation and double heterozygosity increases the risk of tumorigenesis. These findings also benefit understanding of the individual susceptibility to tumor initiation

  2. Mechanisms of increased risk of tumorigenesis in Atm and Brca1 double heterozygosity

    Directory of Open Access Journals (Sweden)

    Wang Jufang

    2011-08-01

    Full Text Available Abstract Background Both epidemiological and experimental studies suggest that heterozygosity for a single gene is linked with tumorigenesis and heterozygosity for two genes increases the risk of tumor incidence. Our previous work has demonstrated that Atm/Brca1 double heterozygosity leads to higher cell transformation rate than single heterozygosity. However, the underlying mechanisms have not been fully understood yet. In the present study, a series of pathways were investigated to clarify the possible mechanisms of increased risk of tumorigenesis in Atm and Brca1 heterozygosity. Methods Wild type cells, Atm or Brca1 single heterozygous cells, and Atm/Brca1 double heterozygous cells were used to investigate DNA damage and repair, cell cycle, micronuclei, and cell transformation after photon irradiation. Results Remarkable high transformation frequency was confirmed in Atm/Brca1 double heterozygous cells compared to wild type cells. It was observed that delayed DNA damage recognition, disturbed cell cycle checkpoint, incomplete DNA repair, and increased genomic instability were involved in the biological networks. Haploinsufficiency of either ATM or BRCA1 negatively impacts these pathways. Conclusions The quantity of critical proteins such as ATM and BRCA1 plays an important role in determination of the fate of cells exposed to ionizing radiation and double heterozygosity increases the risk of tumorigenesis. These findings also benefit understanding of the individual susceptibility to tumor initiation.

  3. PAF-Myc-Controlled Cell Stemness Is Required for Intestinal Regeneration and Tumorigenesis.

    Science.gov (United States)

    Kim, Moon Jong; Xia, Bo; Suh, Han Na; Lee, Sung Ho; Jun, Sohee; Lien, Esther M; Zhang, Jie; Chen, Kaifu; Park, Jae-Il

    2018-03-12

    The underlying mechanisms of how self-renewing cells are controlled in regenerating tissues and cancer remain ambiguous. PCNA-associated factor (PAF) modulates DNA repair via PCNA. Also, PAF hyperactivates Wnt/β-catenin signaling independently of PCNA interaction. We found that PAF is expressed in intestinal stem and progenitor cells (ISCs and IPCs) and markedly upregulated during intestinal regeneration and tumorigenesis. Whereas PAF is dispensable for intestinal homeostasis, upon radiation injury, genetic ablation of PAF impairs intestinal regeneration along with the severe loss of ISCs and Myc expression. Mechanistically, PAF conditionally occupies and transactivates the c-Myc promoter, which induces the expansion of ISCs/IPCs during intestinal regeneration. In mouse models, PAF knockout inhibits Apc inactivation-driven intestinal tumorigenesis with reduced tumor cell stemness and suppressed Wnt/β-catenin signaling activity, supported by transcriptome profiling. Collectively, our results unveil that the PAF-Myc signaling axis is indispensable for intestinal regeneration and tumorigenesis by positively regulating self-renewing cells. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. Interlobular and intralobular mammary stroma: Genotype may not reflect phenotype

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    Meltzer PS

    2008-08-01

    Full Text Available Abstract Background The normal growth and function of mammary epithelial cells depend on interactions with the supportive stroma. Alterations in this communication can lead to the progression or expansion of malignant growth. The human mammary gland contains two distinctive types of fibroblasts within the stroma. The epithelial cells are surrounded by loosely connected intralobular fibroblasts, which are subsequently surrounded by the more compacted interlobular fibroblasts. The different proximity of these fibroblasts to the epithelial cells suggests distinctive functions for these two subtypes. In this report, we compared the gene expression profiles between the two stromal subtypes. Methods Fresh normal breast tissue was collected from reduction mammoplasty patients and immediately placed into embedding medium and frozen on dry ice. Tissue sections were subjected to laser capture microscopy to isolate the interlobular from the intralobular fibroblasts. RNA was prepared and subjected to microarray analysis using the Affymetrix Human Genome U133 GeneChip®. Data was analyzed using the Affy and Limma packages available from Bioconductor. Findings from the microarray analysis were validated by RT-PCR and immunohistochemistry. Results No statistically significant difference was detected between the gene expression profiles of the interlobular and intralobular fibroblasts by microarray analysis and RT-PCR. However, for some of the genes tested, the protein expression patterns between the two subtypes of fibroblasts were significantly different. Conclusion This study is the first to report the gene expression profiles of the two distinct fibroblast populations within the human mammary gland. While there was no significant difference in the gene expression profiles between the groups, there was an obvious difference in the expression pattern of several proteins tested. This report also highlights the importance of studying gene regulation at both the

  5. Identification of Putative Ortholog Gene Blocks Involved in Gestant and Lactating Mammary Gland Development: A Rodent Cross-Species Microarray Transcriptomics Approach

    Science.gov (United States)

    Rodríguez-Cruz, Maricela; Coral-Vázquez, Ramón M.; Hernández-Stengele, Gabriel; Sánchez, Raúl; Salazar, Emmanuel; Sanchez-Muñoz, Fausto; Encarnación-Guevara, Sergio; Ramírez-Salcedo, Jorge

    2013-01-01

    The mammary gland (MG) undergoes functional and metabolic changes during the transition from pregnancy to lactation, possibly by regulation of conserved genes. The objective was to elucidate orthologous genes, chromosome clusters and putative conserved transcriptional modules during MG development. We analyzed expression of 22,000 transcripts using murine microarrays and RNA samples of MG from virgin, pregnant, and lactating rats by cross-species hybridization. We identified 521 transcripts differentially expressed; upregulated in early (78%) and midpregnancy (89%) and early lactation (64%), but downregulated in mid-lactation (61%). Putative orthologous genes were identified. We mapped the altered genes to orthologous chromosomal locations in human and mouse. Eighteen sets of conserved genes associated with key cellular functions were revealed and conserved transcription factor binding site search entailed possible coregulation among all eight block sets of genes. This study demonstrates that the use of heterologous array hybridization for screening of orthologous gene expression from rat revealed sets of conserved genes arranged in chromosomal order implicated in signaling pathways and functional ontology. Results demonstrate the utilization power of comparative genomics and prove the feasibility of using rodent microarrays to identification of putative coexpressed orthologous genes involved in the control of human mammary gland development. PMID:24288657

  6. Can the sentinel lymph node technique affect decisions to offer internal mammary chain irradiation?

    International Nuclear Information System (INIS)

    Bourre, Jean-Cyril; Payan, Raoul; Collomb, Delphine; Gallazzini-Crepin, Celine; Calizzano, Alex; Desruet, Marie-Dominique; Pasquier, Dominique; Bolla, Michel; Fagret, Daniel; Vuillez, Jean-Philippe

    2009-01-01

    Identification of the sentinel lymph node (SLN) for small mammary tumours (cT1N0) sometimes leads to detection of internal mammary chain (IMC) drainage. This information is often ignored by physicians. The present study sought to determine the frequency with which an internal mammary SLN was identified by peritumoral injection of radioactive tracer, and then to determine the patients in whom identification of an internal mammary SLN could have an impact on the radiation treatment plan. Between March 2002 and March 2008, 622 SLN biopsies performed in a cohort of 608 patients were analysed. Technetium-labelled nanocolloids were administered via three peritumoral injections, completed by a deep prepectoral injection, with the entire procedure performed under echographic guidance. The SLN was identified in 607 of the 622 patients, including 174 (28.7%) in the IMC. A total of 161 successful internal mammary biopsies were performed. Of the 622 patients, 18 showed SLN involvement in the IMC. In 7 of these patients, only the internal mammary SLN was affected. Prophylactic irradiation of the IMC was indicated in 376 patients, but only in 18 (4.8%) of these patients was there effectively IMC involvement; internal mammary SLN biopsy failed in 7 patients (1.9%). SLN detection by peritumoral injection, combined with the systematic removal of the internal mammary SLN, enabled the involvement of this region to be found in a nonnegligible number of patients. Such information should make it possible to personalize treatment for patients with stage cT1 mammary cancer and thereby avoid needless internal mammary radiation therapy in a large number of patients (93.4% in our study). (orig.)

  7. Internal mammary artery aneurysm in Marfan syndrome: case report

    Energy Technology Data Exchange (ETDEWEB)

    Common, A A; Pressacco, J; Wilson, J K [Univ. of Toronto, Dept. of Mecial Imaging, Toronto, Ontario (Canada)

    1999-02-01

    Marfan syndrome has a pleomorphic phenotype. Those affected have abnormalities in the eyes and in the nervous, cardiovascular and musculoskeletal systems. Among these abnormalities are many reported aneurysms, involving the ascending, descending thoracic and abdominal aorta, the sinus of Valsalva, and the internal carotid artery. We report a left internal mammary artery (LIMA) aneurysm in a patient with Marfan syndrome and no other known predisposition to such an aneurysm. No other case of LIMA aneurysm in Marfan syndrome has, to our knowledge, been reported. (author)

  8. Internal mammary artery aneurysm in Marfan syndrome: case report

    International Nuclear Information System (INIS)

    Common, A.A.; Pressacco, J.; Wilson, J.K.

    1999-01-01

    Marfan syndrome has a pleomorphic phenotype. Those affected have abnormalities in the eyes and in the nervous, cardiovascular and musculoskeletal systems. Among these abnormalities are many reported aneurysms, involving the ascending, descending thoracic and abdominal aorta, the sinus of Valsalva, and the internal carotid artery. We report a left internal mammary artery (LIMA) aneurysm in a patient with Marfan syndrome and no other known predisposition to such an aneurysm. No other case of LIMA aneurysm in Marfan syndrome has, to our knowledge, been reported. (author)

  9. Brachial edema after treatment of mammary carcinoma. Significance of phlebography

    Energy Technology Data Exchange (ETDEWEB)

    Botsch, H; Soerensen, R [Freie Univ. Berlin (Germany, F.R.). Klinik fuer Radiologie, Nuklearmedizin und Physikalische Therapie

    1977-01-01

    The frequency of thromboses or of obstacles to the venous flow in brachial or axillary regions has been examined by a phlebographic survey of 102 patients who were treated surgically and radiotherapeutically because of cancers of the breast. Thromboses or venous obstruction were found in the 86 patients with brachial edema. Ten of the patients with brachial edema had thromboses. Further 15 suffered from an obstruction to the venous flow. The results are discussed in detail, and compared with the rather contradictory data in literature. As a consequence of this study an indication for brachial phlebography would be justified on a larger scale with patients having been treated surgically because of mammary carcinoma.

  10. Essential role of miR-200c in regulating self-renewal of breast cancer stem cells and their counterparts of mammary epithelium

    International Nuclear Information System (INIS)

    Feng, Zhong-Ming; Qiu, Jun; Chen, Xie-Wan; Liao, Rong-Xia; Liao, Xing-Yun; Zhang, Lu-Ping; Chen, Xu; Li, Yan; Chen, Zheng-Tang; Sun, Jian-Guo

    2015-01-01

    Breast cancer stem cells (BCSCs) have been reported as the origin of breast cancer and the radical cause of drug resistance, relapse and metastasis in breast cancer. BCSCs could be derived from mutated mammary epithelial stem cells (MaSCs). Therefore, comparing the molecular differences between BCSCs and MaSCs may clarify the mechanism underlying breast carcinogenesis and the targets for gene therapy. Specifically, the distinct miRNome data of BCSCs and MaSCs need to be analyzed to find out the key miRNAs and reveal their roles in regulating the stemness of BCSCs. MUC1 − ESA + cells were isolated from normal mammary epithelial cell line MCF-10A by fluorescence-activated cell sorting (FACS) and tested for stemness by clonogenic assay and multi-potential differentiation experiments. The miRNA profiles of MaSCs, BCSCs and breast cancer MCF-7 cells were compared to obtain the candidate miRNAs that may regulate breast tumorigenesis. An miRNA consecutively upregulated from MaSCs to BCSCs to MCF-7 cells, miR-200c, was chosen to determine its role in regulating the stemness of BCSCs and MaSCs in vitro and in vivo. Based on bioinformatics, the targets of miR-200c were validated by dual-luciferase report system, western blot and rescue experiments. In a 2-D clonogenic assay, MUC1 − ESA + cells gave rise to multiple morphological colonies, including luminal colonies, myoepithelial colonies and mixed colonies. The clonogenic potential of MUC1 − ESA + (61.5 ± 3.87 %) was significantly higher than that of non-stem MCF-10A cells (53.5 ± 3.42 %) (P < 0.05). In a 3-D matrigel culture, MUC1 − ESA + cells grew into mammospheres with duct-like structures. A total of 12 miRNAs of interest were identified, 8 of which were upregulated and 4 downregulated in BCSCs compared with MaSCs. In gain- and lost-of-function assays, miR-200c was sufficient to inhibit the self-renewal of BCSCs and MaSCs in vitro and the growth of BCSCs in vivo. Furthermore, miR-200c negatively regulated

  11. MicroRNAs in the development and neoplasia of the mammary gland [version 1; referees: 1 approved, 2 approved with reservations

    Directory of Open Access Journals (Sweden)

    Manoj Kumar Jena

    2017-06-01

    Full Text Available Study on the role of microRNAs (miRs as regulators of gene expression through posttranscriptional gene silencing is currently gaining much interest,due to their wide involvement in different physiological processes. Understanding mammary gland development, lactation, and neoplasia in relation to miRs is essential. miR expression profiling of the mammary gland from different species in various developmental stages shows their role as critical regulators of development. miRs such as miR-126, miR-150, and miR-145 have been shown to be involved in lipid metabolism during lactation. In addition, lactogenic hormones influence miR expression as evidenced by overexpression of miR-148a in cow mammary epithelial cells, leading to enhanced lactation. Similarly, the miR-29 family modulates lactation-related gene expression by regulating DNA methylation of their promoters. Besides their role in development, lactation and involution, miRs are responsible for breast cancer development. Perturbed estrogen (E2 signaling is one of the major causes of breast cancer. Increased E2 levels cause altered expression of ERα, and ERα-miR cross-talk promotes tumour progression. miRs, such as miR-206, miR-34a, miR-17-5p, and miR-125 a/b are found to be tumour suppressors; whereas miR-21, miR-10B, and miR-155 are oncogenes.Studies using an ACI rat model showed similar findings of miR dysregulation due to excess E2, and a natural phenol antioxidant ellagic acid showed therapeutic properties by reversing the miR dysregulation. This review focuses on the recent findings concerning the role of miRs in developmental stages of the mammary gland (mainly lactation and involution stages and their involvement in breast cancer progression. Further studies in this area will help us understand the molecular details of mammary gland biology,as well as miRs that could be therapeutic targets of breast cancer.

  12. Mammary cancer in man: analysis of 22 cases

    International Nuclear Information System (INIS)

    Viola Alles, A.; Notejane, R.; Signorelli, S.; Muse, I.

    1997-01-01

    22 cases of male patients,averaging 63 years of age(ranging 50-80)were diagnosed as mammary cancer carriers. None of them presented a clear risk factor. Three of them had family history of mammary cancer in females. The clinical presentation was 27.2% E I, 27,2% E II, 30% E III and 13% E IV. In most cases consulting was late, with an average delay of 10 months.Pathology corresponded an infiltrating ductal form in 19 cases, non-infiltrating ductal form in 2 cases and ductal in situ non infiltrating form in 1 case. Dosification of hormonal receptor was not carried out in any of these patients. Regional treatment consisted in surgery plus radiotherapy. Modified radical mastectomy predominated in 12 cases,mastectomy in 6 cases and cuadrantectomy in 2 cases. Two cases were considered non surgical. Techniques and dadiatin doses were conventional. Systemic treatments consisted in tamoxifen o or poli chemotherapy CMF type in 'adyuvancia' cases and tamoxifen o of poli chemotherapy FAC type in the metastatic forms. It was concluded that there is a need of hysthological confirmation of this type of tumor as well as the compulsory dosification of hormonal receptors in order to determine the therapeutic strategy [es

  13. Aberrant E-cadherin staining patterns in invasive mammary carcinoma

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    Brogi Edi

    2005-11-01

    Full Text Available Abstract Background E-cadherin, a cell surface protein involved in cell adhesion, is present in normal breast epithelium, benign breast lesions, and in breast carcinoma. Alterations in the gene CDH1 on chromosome 16q22 are associated with changes in E-cadherin protein expression and function. Inactivation of E-cadherin in lobular carcinomas and certain diffuse gastric carcinomas may play a role in the dispersed, discohesive "single cell" growth patterns seen in these tumors. The molecular "signature" of mammary lobular carcinomas is the loss of E-cadherin protein expression as evidenced by immunohistochemistry, whereas ductal carcinomas are typically E-cadherin positive. Patients and methods We report on E-cadherin immunostaining patterns in five cases of invasive mammary carcinoma Results These were five exceptional instances in which the E-cadherin immunophenotype did not correspond to the apparent histologic classification of the lesion. These cases which are exceedingly rare in our experience are the subject of this report. Conclusion Findings such as those illustrated in this study occur in virtually all biologic phenomena and they do not invalidate the very high degree of correlation between the expression of E-cadherin and the classification of breast carcinomas as ductal or lobular type on the basis of conventional histologic criteria.

  14. PHYLLOID TUMORS OF MAMMARY GLANDS. CURRENT STATE OF THE PROBLEM

    Directory of Open Access Journals (Sweden)

    A. D. Zikiryakhodzhaev

    2017-01-01

    Full Text Available Phylloid (leaf-shaped breast tumors are a rare disease and constitute 0.3–0.5% of all breast tumors. Due to the rare frequency of occurrence, as well as the small number of randomized studies that have been conducted on this pathology, there is currently no standardized approach to the diagnosis and treatment of phylloid tumors. The reports about these rare cases appearing in the literature are, as a rule, descriptive, which only emphasizes the difficulty of differential diagnosis, the development of the correct tactics for treating such patients. In connection with the rarity, it is very difficult to diagnose correctly this pathology, which requires a highly qualified doctor as a diagnostician in the initial contact with such a patient, and a pathologist doctor who establishes the final morphological diagnosis. Often, leaf-shaped tumors are mistaken for mammary fibroadenomas. Such difficulties in correct diagnosis in the preoperative period can lead to errors in the planning of treatment. Also, the recommendations for the treatment of patients with this diagnosis are not fully understood, since up to now there are no accepted treatment standards in both Russian and foreign recommendations. Due to the fact that this pathology of mammary glands is rare, the principles of treatment are based on small retrospective studies and clinical observations. In this review, we will discuss the results of major retrospective studies, including data on epidemiology, etiology, diagnostic approach, strategies and results of treatment of this complex group of breast pathologies.

  15. Radioprotective action of curcumin extracted from Curcuma longa LINN: inhibitory effect on formation of urinary 8-hydroxy-2'-deoxyguanosine, tumorigenesis, but not mortality, induced by γ-ray irradiation

    International Nuclear Information System (INIS)

    Inano, Hiroshi; Onoda, Makoto

    2002-01-01

    Purpose: We evaluated the radioprotective action of curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] extracted from Curcuma longa LINN against the acute and chronic effects and the mortality induced by exposure to radiation using female rats. Methods and Materials: For the assay of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine, a marker for acute effects, Wistar-MS virgin rats were fed the basal diet with exposure at 0 or 3 Gy to γ-rays from a 60 Co source as the control. Rats in the experimental groups received whole-body irradiation with 3 Gy and were fed a diet containing 1% (wt/wt) curcumin for 3 days before and/or 2 days after irradiation. The urine was collected for a 24-h period between 1 and 2 days after irradiation. Urine samples were used to determine the 8-OHdG level using an enzyme-linked immunosorbent assay and the creatinine level by a modified Jaffe reaction. For long-term effects, rats at Day 17 of pregnancy were fed a diet containing curcumin for 3 days before and/or 3 days after irradiation with 1.5 Gy, and received a pellet of diethylstilbestrol as the promoter. The rats were examined for mammary and pituitary tumors for 1 year. To determine survival, virgin rats received whole-body irradiation with 9.6 Gy and were fed a diet containing curcumin for 3 days before and/or 3 days after irradiation. After irradiation, all rats were assessed daily for survival for 30 days. Results: Acutely in virgin rats irradiated with 3 Gy, the creatinine-corrected concentration and total amount of 8-OHdG in the 24-h urine samples were higher (approximately 1.3-fold) than the corresponding values in the nonirradiated controls. Adding curcumin to the diet for 3 days before and/or 2 days after irradiation reduced the elevated 8-OHdG levels by 50-70%. The evaluation of the protective action of curcumin against the long-term effects revealed that curcumin significantly decreased the incidence of mammary and pituitary tumors. However, the

  16. Targeted overexpression of EZH2 in the mammary gland disrupts ductal morphogenesis and causes epithelial hyperplasia.

    Science.gov (United States)

    Li, Xin; Gonzalez, Maria E; Toy, Katherine; Filzen, Tracey; Merajver, Sofia D; Kleer, Celina G

    2009-09-01

    The Polycomb group protein enhancer of zeste homolog 2 (EZH2), which has roles during development of numerous tissues, is a critical regulator of cell type identity. Overexpression of EZH2 has been detected in invasive breast carcinoma tissue samples and is observed in human breast tissue samples of morphologically normal lobules up to 12 years before the development of breast cancer. The function of EZH2 during preneoplastic progression in the mammary gland is unknown. To investigate the role of EZH2 in the mammary gland, we targeted the expression of EZH2 to mammary epithelial cells using the mouse mammary tumor virus long terminal repeat. EZH2 overexpression resulted in aberrant terminal end bud architecture. By the age of 4 months, 100% of female mouse mammary tumor virus-EZH2 virgin mice developed intraductal epithelial hyperplasia resembling the human counterpart accompanied by premature differentiation of ductal epithelial cells and up-regulation of the luminal marker GATA-3. In addition, remodeling of the mammary gland after parturition was impaired and EZH2 overexpression caused delayed involution. Mechanistically, we found that EZH2 physically interacts with beta-catenin, inducing beta-catenin nuclear accumulation in mammary epithelial cells and activating Wnt/beta-catenin signaling. The biological significance of these data to human hyperplasias is demonstrated by EZH2 up-regulation and colocalization with beta-catenin in human intraductal epithelial hyperplasia, the earliest histologically identifiable precursor of breast carcinoma.

  17. Gastrointestinal parasite control during prepuberty improves mammary parenchyma development in Holstein heifers.

    Science.gov (United States)

    Perri, Adrián F; Mejía, Miguel E; Licoff, Nicolás; Diab, Santiago S; Formía, Néstor; Ornstein, Ana; Becú-Villalobos, Damasia; Lacau-Mengido, Isabel M

    2013-12-06

    Parasitism during development impairs normal growth and delays the onset of puberty through altered hormone profiles, including insulin-like growth factor one (IGF-1). As mammary gland development during prepuberty is strongly dependent on IGF-1, we determined if antiparasitic treatment during this stage of growth improved mammary gland development. One group of Holstein heifers was treated monthly, rotationally with antiparasitic drugs from birth to 70 weeks of age, a second group was untreated. Treated heifer calves had between 56% and 65% less EPG counts than untreated ones. Presence of Ostertagia, Cooperia, Haemonchus and Trichostrongylus was demonstrated. Treatment effectively advanced the onset of puberty and increased IGF-1 levels. At 20, 30, 40 and 70 weeks of age biopsies from the mammary gland were taken and histological sections were prepared and stained with hematoxylin-eosin. Pictures were analyzed to compare parenchyma area in relation to total mammary tissue between groups. Mammary samples from treated heifers had higher ratios of parenchyma/total area than untreated ones. As mammary development during prepuberty is crucial for mammary performance during lactation, these results add new evidence to the importance of gastrointestinal parasite control in heifers. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. ATM is required for SOD2 expression and homeostasis within the mammary gland.

    Science.gov (United States)

    Dyer, Lisa M; Kepple, Jessica D; Ai, Lingbao; Kim, Wan-Ju; Stanton, Virginia L; Reinhard, Mary K; Backman, Lindsey R F; Streitfeld, W Scott; Babu, Nivetha Ramesh; Treiber, Nicolai; Scharffetter-Kochanek, Karin; McKinnon, Peter J; Brown, Kevin D

    2017-12-01

    ATM activates the NF-κB transcriptional complex in response to genotoxic and oxidative stress. The purpose of this study was to examine if the NF-κB target gene and critical antioxidant SOD2 (MnSOD) in cultured mammary epithelium is also ATM-dependent, and what phenotypes arise from deletion of ATM and SOD2 within the mammary gland. SOD2 expression was studied in human mammary epithelial cells and MCF10A using RNAi to knockdown ATM or the NF-κB subunit RelA. To study ATM and SOD2 function in mammary glands, mouse lines containing Atm or Sod2 genes containing LoxP sites were mated with mice harboring Cre recombinase under the control of the whey acidic protein promoter. Quantitative PCR was used to measure gene expression, and mammary gland structure was studied using histology. SOD2 expression is ATM- and RelA-dependent, ATM knockdown renders cells sensitive to pro-oxidant exposure, and SOD mimetics partially rescue this sensitivity. Mice with germline deletion of Atm fail to develop mature mammary glands, but using a conditional knockout approach, we determined that Atm deletion significantly diminished the expression of Sod2. We also observed that these mice (termed Atm Δ/Δ ) displayed a progressive lactation defect as judged by reduced pup growth rate, aberrant lobulo-alveolar structure, diminished milk protein gene expression, and increased apoptosis within lactating glands. This phenotype appears to be linked to dysregulated Sod2 expression as mammary gland-specific deletion of Sod2 phenocopies defects observed in Atm Δ/Δ dams. We conclude that ATM is required to promote expression of SOD2 within the mammary epithelium, and that both ATM and SOD2 play a crucial role in mammary gland homeostasis.

  19. From genes to milk: genomic organization and epigenetic regulation of the mammary transcriptome.

    Science.gov (United States)

    Lemay, Danielle G; Pollard, Katherine S; Martin, William F; Freeman Zadrowski, Courtneay; Hernandez, Joseph; Korf, Ian; German, J Bruce; Rijnkels, Monique

    2013-01-01

    Even in genomes lacking operons, a gene's position in the genome influences its potential for expression. The mechanisms by which adjacent genes are co-expressed are still not completely understood. Using lactation and the mammary gland as a model system, we explore the hypothesis that chromatin state contributes to the co-regulation of gene neighborhoods. The mammary gland represents a unique evolutionary model, due to its recent appearance, in the context of vertebrate genomes. An understanding of how the mammary gland is regulated to produce milk is also of biomedical and agricultural importance for human lactation and dairying. Here, we integrate epigenomic and transcriptomic data to develop a comprehensive regulatory model. Neighborhoods of mammary-expressed genes were determined using expression data derived from pregnant and lactating mice and a neighborhood scoring tool, G-NEST. Regions of open and closed chromatin were identified by ChIP-Seq of histone modifications H3K36me3, H3K4me2, and H3K27me3 in the mouse mammary gland and liver tissue during lactation. We found that neighborhoods of genes in regions of uniquely active chromatin in the lactating mammary gland, compared with liver tissue, were extremely rare. Rather, genes in most neighborhoods were suppressed during lactation as reflected in their expression levels and their location in regions of silenced chromatin. Chromatin silencing was largely shared between the liver and mammary gland during lactation, and what distinguished the mammary gland was mainly a small tissue-specific repertoire of isolated, expressed genes. These findings suggest that an advantage of the neighborhood organization is in the collective repression of groups of genes via a shared mechanism of chromatin repression. Genes essential to the mammary gland's uniqueness are isolated from neighbors, and likely have less tolerance for variation in expression, properties they share with genes responsible for an organism's survival.

  20. Transfer of milk prolactin ro the plasma of neonatal rats by intestinal absorption

    Energy Technology Data Exchange (ETDEWEB)

    Whitworth, N S; Grosvenor, C E [Tennessee Univ., Memphis (USA). Dept. of Physiology and Biophysics

    1978-11-01

    Prolactin passes from the systemic circulation of lactating rats into the milk where it can be consumed by the young rats during suckling. /sup 131/- labelled rat prolactin was detected in the plasma of 9- to 14-day-old rats after being nursed by mothers previously injected with /sup 131/I-labelled rat prolactin and after the pups had received /sup 131/I-labelled rat prolactin by gastric intubation. It was estimated that 16% of the /sup 131/I-labelled rat prolactin given by gastric intubation subsequently appeared in the plasma of the neonate. Gastric administration of 10.5 or 21.0 ..mu..g B-1 rat prolactin significantly raised the level of prolactin in the plasma of 13-day-old pups, but a similar increase was not observed when 27-day-old rats were given 46.2 ..mu..g B-1 prolactin by gastric intubation. The concentration of prolactin in the plasma of 13-to 14-day-old rats rose to 55 ng/ml 30 min after the onset of nursing by mothers whose mammary glands were full of milk, whereas the concentration in the plasma of mothers with empty mammary glands remained at basal values. It is concluded that the intestine of the newborn is permeable to prolactin and that milk may constitute an exogeneous source of prolactin for the suckled offspring.

  1. Mifepristone inhibits MPA-and FGF2-induced mammary tumor growth but not FGF2-induced mammary hyperplasia

    Directory of Open Access Journals (Sweden)

    Juan P. Cerliani

    2010-12-01

    Full Text Available We have previously demonstrated a crosstalk between fibroblast growth factor 2 (FGF2 and progestins inducing experimental breast cancer growth. The aim of the present study was to compare the effects of FGF2 and of medroxyprogesterone acetate (MPA on the mouse mammary glands and to investigate whether the antiprogestin RU486 was able to reverse the MPA- or FGF2-induced effects on both, mammary gland and tumor growth. We demonstrate that FGF2 administered locally induced an intraductal hyperplasia that was not reverted by RU486, suggesting that FGF2-induced effects are progesterone receptor (PR-independent. However, MPA-induced paraductal hyperplasia was reverted by RU486 and a partial agonistic effect was observed in RU486-treated glands. Using C4-HD tumors which only grow in the presence of MPA, we showed that FGF2 administered intratumorally was able to stimulate tumor growth as MPA. The histology of FGF2-treated tumors showed different degrees of gland differentiation. RU486 inhibited both, MPA or FGF2 induced tumor growth. However, only complete regression was observed in MPA-treated tumors. Our results support the hypothesis that stromal FGF2 activates PR inducing hormone independent tumor growth.

  2. 78. Coronary bypass using bilateral internal mammary arteries in an achondroplast

    Directory of Open Access Journals (Sweden)

    Mohamed Abdulwahab Alassal

    2015-10-01

    Full Text Available Coronary bypass grafting for ischemic heart disease in achondroplastic dwarfs is very rare. Shortage of veins and sometimes, inadequate vein quality can cause difficulties during surgery. Only two achondroplastic cases were reported in literature that underwent coronary bypass surgery, in which the left internal mammary artery and vein grafts were used. To the best of our knowledge using bilateral internal mammary arteries in such patients was not reported. We report here a 55 years old male achondroplastic dwarf who had triple vessels coronary disease that underwent successful coronary bypass surgery using bilateral mammary arteries. Anatomic and surgical challenges in achondroplasia are highlighted

  3. ELEVATED TRANS-MAMMARY TRANSMISSION OF Toxocara canis LARVAE IN BALB/c MICE

    Directory of Open Access Journals (Sweden)

    Paula de Lima Telmo

    2015-02-01

    Full Text Available Toxocariasis is a widespread zoonosis and is considered an important worldwide public health problem. The aim of this study was to investigate the frequency of trans-mammary Toxocara canis infection in newborn BALB/c mice nursed by females experimentally infected with 1,200 eggs after delivery. After 50 days of age, the presence of larvae in different organs of the offspring was investigated. Trans-mammary infection was confirmed in 73.9% of the mice that had been nursed by infected females. These data show a high trans-mammary transmission of T. canis and confirm the significance of this transmission route in paratenic hosts.

  4. Molecular mechanisms involved in casein gene expression and secretion in mouse mammary epithelial cells

    International Nuclear Information System (INIS)

    Lee, E.Y.H.P.; Lee, W.H.; Parry, G.; Bissell, M.J.

    1985-01-01

    Mouse mammary epithelial cells (MMEC) secrete a group of milk-specific proteins including various caseins and whey proteins. Dissociated mammary epithelial cells maintain expression of most of their differentiated functions only if cells are plated on a suitable substratum. Casein production and section, cell morphology, and production of α-lactalbumin have been used as markers to assess the degree of differentiation of mammary cells in culture. The general consensus is that cells express their differentiated properties at high levels and for longer periods of time on such substrata. In this paper, the authors demonstrate that modulation of the expression of caseins by floating collagen gels is manifested at several regulatory points

  5. Phosphorylation of Nanog is Essential to Regulate Bmi1 and Promote Tumorigenesis

    Science.gov (United States)

    Xie, Xiujie; Piao, Longzhu; Cavey, Greg S.; Old, Matthew; Teknos, Theodoros N.; Mapp, Anna K; Pan, Quintin

    2014-01-01

    Emerging evidence indicates that Nanog is intimately involved in tumorigenesis in part through regulation of the cancer initiating cell population. However, the regulation and role of Nanog in tumorigenesis are still poorly understood. In this study, human Nanog was identified to be phosphorylated by human PKCε at multiple residues including T200 and T280. Our work indicated that phosphorylation at T200 and T280 modulates Nanog function through several regulatory mechanisms. Results with phosphorylation-insensitive and phosphorylation-mimetic mutant Nanog revealed that phosphorylation at T200 and T280 enhance Nanog protein stability. Moreover, phosphorylation-insensitive T200A and T280A mutant Nanog had a dominant-negative function to inhibit endogenous Nanog transcriptional activity. Inactivation of Nanog was due to impaired homodimerization, DNA binding, promoter occupancy, and p300, a transcriptional co-activator, recruitment resulting in a defect in target gene promoter activation. Ectopic expression of phosphorylation-insensitive T200A or T280A mutant Nanog reduced cell proliferation, colony formation, invasion, migration, and the cancer initiating cell population in head and neck squamous cell carcinoma (HNSCC) cells. The in vivo cancer initiating ability was severely compromised in HNSCC cells expressing phosphorylation-insensitive T200A or T280A mutant Nanog; 87.5% (14/16), 12.5% (1/8), and 0% (0/8) for control, T200A, and T280A, respectively. Nanog occupied the Bmi1 promoter to directly transactivate and regulate Bmi1. Genetic ablation and rescue experiments demonstrated that Bmi1 is a critical downstream signaling node for the pleiotropic, pro-oncogenic effects of Nanog. Taken together, our study revealed, for the first time, that post-translational phosphorylation of Nanog is essential to regulate Bmi1 and promote tumorigenesis. PMID:23708658

  6. Kaiso overexpression promotes intestinal inflammation and potentiates intestinal tumorigenesis in Apc(Min/+) mice.

    Science.gov (United States)

    Pierre, Christina C; Longo, Joseph; Mavor, Meaghan; Milosavljevic, Snezana B; Chaudhary, Roopali; Gilbreath, Ebony; Yates, Clayton; Daniel, Juliet M

    2015-09-01

    Constitutive Wnt/β-catenin signaling is a key contributor to colorectal cancer (CRC). Although inactivation of the tumor suppressor adenomatous polyposis coli (APC) is recognized as an early event in CRC development, it is the accumulation of multiple subsequent oncogenic insults facilitates malignant transformation. One potential contributor to colorectal carcinogenesis is the POZ-ZF transcription factor Kaiso, whose depletion extends lifespan and delays polyp onset in the widely used Apc(Min/+) mouse model of intestinal cancer. These findings suggested that Kaiso potentiates intestinal tumorigenesis, but this was paradoxical as Kaiso was previously implicated as a negative regulator of Wnt/β-catenin signaling. To resolve Kaiso's role in intestinal tumorigenesis and canonical Wnt signaling, we generated a transgenic mouse model (Kaiso(Tg/+)) expressing an intestinal-specific myc-tagged Kaiso transgene. We then mated Kaiso(Tg/+) and Apc(Min/+) mice to generate Kaiso(Tg/+):Apc(Min/+) mice for further characterization. Kaiso(Tg/+):Apc(Min/+) mice exhibited reduced lifespan and increased polyp multiplicity compared to Apc(Min/+) mice. Consistent with this murine phenotype, we found increased Kaiso expression in human CRC tissue, supporting a role for Kaiso in human CRC. Interestingly, Wnt target gene expression was increased in Kaiso(Tg/+):Apc(Min/+) mice, suggesting that Kaiso's function as a negative regulator of canonical Wnt signaling, as seen in Xenopus, is not maintained in this context. Notably, Kaiso(Tg/+):Apc(Min/+) mice exhibited increased inflammation and activation of NFκB signaling compared to their Apc(Min/+) counterparts. This phenotype was consistent with our previous report that Kaiso(Tg/+) mice exhibit chronic intestinal inflammation. Together our findings highlight a role for Kaiso in promoting Wnt signaling, inflammation and tumorigenesis in the mammalian intestine. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Suppression of colorectal tumorigenesis by recombinant Bacteroides fragilis enterotoxin-2 in vivo

    OpenAIRE

    Lv, You; Ye, Tao; Wang, Hui-Peng; Zhao, Jia-Ying; Chen, Wen-Jie; Wang, Xin; Shen, Chen-Xia; Wu, Yi-Bin; Cai, Yuan-Kun

    2017-01-01

    AIM To evaluate the impact of recombinant Bacteroides fragilis enterotoxin-2 (BFT-2, or Fragilysin) on colorectal tumorigenesis in mice induced by azoxymethane/dextran sulfate sodium (AOM/DSS). METHODS Recombinant proBFT-2 was expressed in Escherichia coli strain Rosetta (DE3) and BFT-2 was obtained and tested for its biological activity via colorectal adenocarcinoma cell strains SW-480. Seventy C57BL/6J mice were randomly divided into a blank (BC; n = 10), model (AD; n = 20), model + low-dos...

  8. Retinoblastoma pathway defects show differential ability to activate the constitutive DNA damage response in human tumorigenesis

    DEFF Research Database (Denmark)

    Tort, F.; Bartkova, J.; Sehested, M.

    2006-01-01

    culture models with differential defects of retinoblastoma pathway components, as overexpression of cyclin D1 or lack of p16(Ink4a), either alone or combined, did not elicit detectable DDR. In contrast, inactivation of pRb, the key component of the pathway, activated the DDR in cultured human or mouse...... with their hierarchical positions along the retinoblastoma pathway. Our data provide new insights into oncogene-evoked DDR in human tumorigenesis, with potential implications for individualized management of tumors with elevated cyclin D1 versus cyclin E, due to their distinct clinical variables and biological behavior....

  9. Interleukin 21 controls tumour growth and tumour immunosurveillance in colitis-associated tumorigenesis in mice.

    Science.gov (United States)

    Jauch, Dominik; Martin, Maria; Schiechl, Gabriela; Kesselring, Rebecca; Schlitt, Hans Jürgen; Geissler, Edward K; Fichtner-Feigl, Stefan

    2011-12-01

    Colitis-associated tumorigenesis is a balance between proliferation of tumour cells and tumour immunosurveillance. The role of T-helper-cell-derived cytokines in tumour growth is not fully understood. In this study the authors investigated the influence of interleukin (IL) 21 on intestinal tumorigenesis. Chronic colitis was induced in IL-21(-/-) and littermate control wild-type mice with three cycles of 1.5% dextran sulphate sodium (DSS) over 7 days followed by 7 days of drinking water. Mice received an azoxymethane injection on day 0 of DSS-colitis to induce tumorigenesis. Immunohistochemistry was performed on inflamed and tumour-bearing areas of colons. Cytokine expression of isolated colonic CD4 T cells was determined by ELISA. Cytotoxic capacity of isolated colonic CD8 T cells targeting tumour cells was evaluated by flow cytometry and quantitative cytotoxicity assay. Apoptosis of tumour cells was determined by TUNEL assay of colonic sections. Increasing expression of IL-21 was observed in chronic colitis, which showed functional importance, since IL-21 deficiency prevented chronic DSS-colitis development. Further, in the absence of IL-21, significantly fewer tumour nodules were detected, despite a similar extent of intestinal inflammation. In wild-type mice, 8.6±1.9 tumour nodules were found compared with 1.0±1.2 in IL-21-deficient mice. In tumour-bearing IL-21-deficient mice, intestinal inflammation was restored and partly dependent on interferon (IFN)-γ, whereas the inflammation in wild-type mice showed high IL-17A concentrations. In these rare tumours in IL-21-deficient mice, tumour cell proliferation (Ki-67) was decreased, while cell apoptosis was increased, compared with wild-type mice. Increased IFNγ expression in tumour-bearing IL-21-deficient mice led to increased tumour immunosurveillance mediated by cytotoxic CD8CD103 T cells targeting E-cadherin(+) colonic tumour cells and therefore limited tumour growth. These results indicate that IL-21

  10. Transgenic mouse models of hormonal mammary carcinogenesis: advantages and limitations.

    Science.gov (United States)

    Kirma, Nameer B; Tekmal, Rajeshwar R

    2012-09-01

    Mouse models of breast cancer, especially transgenic and knockout mice, have been established as valuable tools in shedding light on factors involved in preneoplastic changes, tumor development and malignant progression. The majority of mouse transgenic models develop estrogen receptor (ER) negative tumors. This is seen as a drawback because the majority of human breast cancers present an ER positive phenotype. On the other hand, several transgenic mouse models have been developed that produce ER positive mammary tumors. These include mice over-expressing aromatase, ERα, PELP-1 and AIB-1. In this review, we will discuss the value of these models as physiologically relevant in vivo systems to understand breast cancer as well as some of the pitfalls involving these models. In all, we argue that the use of transgenic models has improved our understanding of the molecular aspects and biology of breast cancer. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Immunologic aspects of fibrosis in mouse mammary carcinomas.

    Science.gov (United States)

    Vaage, J

    1992-01-02

    The nature of the fibrosis associated with mammary carcinomas MC2 and MC3 was investigated in syngeneic C3H mice. Accelerated and enhanced peri-tumor cellular and fibrotic responses and retarded tumor growth were observed in actively immunized and in adoptively immunized mice, and in mice treated with IL-2. T lymphocytes and, particularly, macrophages were closely associated with collagen deposition at the tumors. The collagen deposition frequently resulted in the encapsulation and regression of the less invasive tumor MC2. A cellular fibrous response was not observed at tumors implanted into athymic C3Hnu/nu mice. The results suggest that tumor fibrosis may in some circumstances be promoted by an immune response.

  12. Assessment of female reproductive endpoints in Sprague-Dawley rats developmentally exposed to Diuron: potential ovary toxicity.

    Science.gov (United States)

    Grassi, Tony Fernando; Guerra, Marina Trevisan; Perobelli, Juliana Elaine; de Toledo, Fabíola Choqueta; da Silva, Denise Salioni; De Grava Kempinas, Wilma; Barbisan, Luís Fernando

    2011-10-01

    Diuron is widely used in agriculture but its deleterious effects on the reproductive system and mammary gland are still poorly understood. This study evaluated whether early-life-stage exposure to Diuron alters puberty onset or susceptibility to mammary carcinogenesis in female Sprague-Dawley rats. Pregnant rats received basal diet or diet containing Diuron at 500, 750, and 1,250 ppm, from gestational day 12 to the end of lactation (postnatal day 21 [PND21]). After weaning, female offspring continued receiving basal diet or diet containing Diuron until PND 51. At PND 51, female Sprague-Dawley offspring received a single dose of 50 mg/kg b.w. of 7,12-dimethylbenz(a)anthracene (DMBA) for initiation of mammary carcinogenesis. The animals were sacrificed on PND 51, 75, and 226 to 233 (week 25) for mammary gland morphology, reproductive organs and tumor analysis, respectively. There were no significant differences among groups on vaginal opening, estrous cycle, mammary morphology, or carcinogenesis. However, reductions in ovary weight and corpora lutea were observed at PND 75 in the group treated with Diuron at 1,250 ppm. The findings suggesting that Diuron exposure (1,250 ppm) may have been potentially toxic to the ovaries. © 2011 Wiley Periodicals, Inc.

  13. Cyclin D1 and mammary carcinoma: new insights from transgenic mouse models

    International Nuclear Information System (INIS)

    Sutherland, Robert L; Musgrove, Elizabeth A

    2002-01-01

    Cyclin D1 is one of the most commonly overexpressed oncogenes in breast cancer, with 45–50% of primary ductal carcinomas overexpressing this oncoprotein. Targeted deletion of the gene encoding cyclin D1 demonstrates an essential role in normal mammary gland development while transgenic studies provide evidence that cyclin D1 is a weak oncogene in mammary epithelium. In a recent exciting development, Yu et al. demonstrate that cyclin D1-deficient mice are resistant to mammary carcinomas induced by c-neu and v-Ha-ras, but not those induced by c-myc or Wnt-1. These findings define a pivotal role for cyclin D1 in a subset of mammary cancers in mice and imply a functional role for cyclin D1 overexpression in human breast cancer

  14. Tubulopapillary carcinoma of the mammary gland in a maned wolf (Chrysocyon brachyurus: histopathological and immunophenotypical analysis

    Directory of Open Access Journals (Sweden)

    C.O. Gamba

    2011-12-01

    Full Text Available A maned female wolf (Chrysocyon brachyurus showed nodules in the inguinal and left abdominal cranial mammary glands. The mammary gland was surgically excised, and microscopic analysis revealed epithelial cell proliferation in a tubular and papillary pattern; delicate fibrovascular stalks presenting numerous layers of moderately pleomorfic epithelial cells were observed. This histologic appearance was compatible with a diagnosis of mammary tubulopapillary carcinoma. The immunohistochemical profile revealed nuclear positivity for estrogen (70% and progesterone (at least 90% of the neoplastic cells. The myoepithelium-associated with neoplastic cells lacked integrity, as evidenced by failed smooth muscle alpha actin reactivity in microinvasive areas. A low proliferation index was observed (3.4%. To the authors' knowledge, the present case represents the first finding of female tubulopapillary carcinoma in a mammary gland in this species.

  15. Estrogens in the wrong place at the wrong time: Fetal BPA exposure and mammary cancer.

    Science.gov (United States)

    Paulose, Tessie; Speroni, Lucia; Sonnenschein, Carlos; Soto, Ana M

    2015-07-01

    Iatrogenic gestational exposure to diethylstilbestrol (DES) induced alterations of the genital tract and predisposed individuals to develop clear cell carcinoma of the vagina as well as breast cancer later in life. Gestational exposure of rodents to a related compound, the xenoestrogen bisphenol-A (BPA) increases the propensity to develop mammary cancer during adulthood, long after cessation of exposure. Exposure to BPA during gestation induces morphological alterations in both the stroma and the epithelium of the fetal mammary gland at 18 days of age. We postulate that the primary target of BPA is the fetal stroma, the only mammary tissue expressing estrogen receptors during fetal life. BPA would then alter the reciprocal stroma-epithelial interactions that mediate mammogenesis. In addition to this direct effect on the mammary gland, BPA is postulated to affect the hypothalamus and thus in turn affect the regulation of mammotropic hormones at puberty and beyond. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Control of the Mammary Cell Cycle Clock by Estrogen and Progesterone

    National Research Council Canada - National Science Library

    Weinberg, Robert

    2001-01-01

    Both the growth and the development of the mammary gland are controlled by the female hormones estrogen, prolactin and progesterone, and by interactions between the epithelial and stromal compartments of the breast...

  17. Control of the Mammary Cell Cycle Clock by Estrogen and Progesterone

    National Research Council Canada - National Science Library

    Weinberg, Robert

    1999-01-01

    Both the growth and the development of the mammary gland are controlled by the female hormones estrogen and progesterone, and by interactions between the epithelial and stromal compartments of the breast...

  18. On Cell–Matrix Interactions in Mammary Gland Development and Breast Cancer

    OpenAIRE

    Talhouk, Rabih

    2012-01-01

    Remarkable strides have been made in understanding the role of the extracellular matrix in mammary gland biology. But future efforts should employ a more physiologically relevant model system (i.e., a non-culture-based system).

  19. Wnt-5a and Wnt-4 Regulates Cell Growth in C57MG Mammary Epithelial Cells

    National Research Council Canada - National Science Library

    Olson, Daniel

    1998-01-01

    .... That is, it is important ultimately to understand whether the inappropriate down regulation of certain wnt-genes that are spatially-temporally expressed in developing mammary glands, such as wnt-5a...

  20. Exposure to ionizing radiation induced persistent gene expression changes in mouse mammary gland

    Data.gov (United States)

    National Aeronautics and Space Administration — Six to eight week old female C57BL/6J mice were exposed to 2 Gy of whole body xce xb3 radiation and mammary glands were surgically removed 2-month after radiation....

  1. Genotype x diet interactions in mice predisposed to mammary cancer: II. Tumors and metastasis

    DEFF Research Database (Denmark)

    Gordon, Ryan R; Hunter, Kent W; Merrill, Michele La

    2008-01-01

    either a very high-fat or a matched-control-fat diet, and we measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases. SNP genotyping across the genome facilitated analyses of QTL and QTL × diet interaction effects. Here we describe......High dietary fat intake and obesity may increase the risk of susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F2 mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F2 mice...... effects of diet on mammary tumor and metastases phenotypes, mapping of tumor/metastasis modifier genes, and the interaction between dietary fat levels and effects of cancer modifiers. Results demonstrate that animals fed a high-fat diet are not only more likely to experience decreased mammary cancer...

  2. Prevention and Treatment of Spontaneous Mammary Carcinoma with Dendritic Tumor Fusion Cell Vaccine

    National Research Council Canada - National Science Library

    Gong, Jianlin

    2002-01-01

    In the present study, the prevention of cancer development by vaccination with fusion cells was evaluated In a genetically engineered murine model which develops spontaneous mammary carcinomas. The mice (MMT...

  3. Extensive expression of craniofacial related homeobox genes in canine mammary sarcomas

    NARCIS (Netherlands)

    Wensman, H.; Goransson, H.; Leuchowius, K.J.; Stromberg, S.; Ponten, F.; Isaksson, A.; Rutteman, G.R.; Heldin, N.; Pejler, G.; Hellmen, E.

    2009-01-01

    Extensive expression of craniofacial related homeobox genes in canine mammary sarcomas Journal Breast Cancer Research and Treatment Publisher Springer Netherlands ISSN 0167-6806 (Print) 1573-7217 (Online) Issue Volume 118, Number 2 / November, 2009 Category Preclinical Study DOI

  4. Msx2 Plays a central Role in Regulating Branching Morphogenesis During Mammary Development

    National Research Council Canada - National Science Library

    Liu, Yi-Hsin

    2002-01-01

    The purpose of this study is to determine the role of a transcriptional factor, Msx2, in regulating branching events in the development of the mouse mammary gland To define the function of Msx2 gene...

  5. Accessory mammary tissue associated with congenital and hereditary nephrourinary malformations.

    Science.gov (United States)

    Urbani, C E; Betti, R

    1996-05-01

    The association between polythelia (supernumerary nipple) and kidney and urinary tract malformations (KUTM) is controversial. Some authors reported this association in newborns and infants. Case-control studies dealing with adult subjects are not found in the literature. The purpose of this study is to determine the frequency of the association between accessory mammary tissue (AMT) and congenital and hereditary nephrourinary defects in an adult population compared to a control group. The study was performed in 146 white patients (123 men, 23 women) with AMT out of 2645 subjects consecutively referred to us for physical examination. The following investigations were undertaken: ultrasonographic examination of the abdomen and the kidneys, ECG, echocardiogram, roentgenogram of the vertebral column, urinalysis, and other laboratory tests. A sex- and age-matched control group without any evidence of AMT or lateral displacement of the nipples underwent the same examinations. Kidney and urinary tract malformations were detected in 11 patients with AMT (nine men, two women) and in one control. These data indicate a significantly higher frequency of KUTM in the AMT-affected patients compared to controls (7.53% vs. 0.68%, P < 0.001). A broad spectrum of KUTM was discovered in association with AMT: adult dominant polycystic kidney disease, unilateral renal agenesis, cystic renal dysplasia, familial renal cysts, and congenital stenosis of the pyeloureteral joint. Accessory mammary tissue offers an important clue for congenital and hereditary anomalies of the kidneys and urinary collecting systems. Patients with AMT should, therefore, be extensively examined for the presence of occult nephrouropathies.

  6. Bovine mammary gene expression profiling during the onset of lactation.

    Directory of Open Access Journals (Sweden)

    Yuanyuan Gao

    Full Text Available BACKGROUND: Lactogenesis includes two stages. Stage I begins a few weeks before parturition. Stage II is initiated around the time of parturition and extends for several days afterwards. METHODOLOGY/PRINCIPAL FINDINGS: To better understand the molecular events underlying these changes, genome-wide gene expression profiling was conducted using digital gene expression (DGE on bovine mammary tissue at three time points (on approximately day 35 before parturition (-35 d, day 7 before parturition (-7 d and day 3 after parturition (+3 d. Approximately 6.2 million (M, 5.8 million (M and 6.1 million (M 21-nt cDNA tags were sequenced in the three cDNA libraries (-35 d, -7 d and +3 d, respectively. After aligning to the reference sequences, the three cDNA libraries included 8,662, 8,363 and 8,359 genes, respectively. With a fold change cutoff criteria of ≥ 2 or ≤-2 and a false discovery rate (FDR of ≤ 0.001, a total of 812 genes were significantly differentially expressed at -7 d compared with -35 d (stage I. Gene ontology analysis showed that those significantly differentially expressed genes were mainly associated with cell cycle, lipid metabolism, immune response and biological adhesion. A total of 1,189 genes were significantly differentially expressed at +3 d compared with -7 d (stage II, and these genes were mainly associated with the immune response and cell cycle. Moreover, there were 1,672 genes significantly differentially expressed at +3 d compared with -35 d. Gene ontology analysis showed that the main differentially expressed genes were those associated with metabolic processes. CONCLUSIONS: The results suggest that the mammary gland begins to lactate not only by a gain of function but also by a broad suppression of function to effectively push most of the cell's resources towards lactation.

  7. Bilateral Internal Mammary Artery Utilization in Diabetics: Friend or Foe?

    Science.gov (United States)

    Crawford, Todd C; Zhou, Xun; Fraser, Charles D; Magruder, J Trent; Suarez-Pierre, Alejandro; Alejo, Diane; Bobbitt, Jennifer; Fonner, Clifford E; Wehberg, Kurt; Taylor, Brad; Kwon, Christopher; Fiocco, Michael; Conte, John V; Salenger, Rawn; Whitman, Glenn J

    2018-05-11

    Bilateral internal mammary artery (BIMA) grafting in diabetic patients undergoing coronary artery bypass grafting (CABG) remains controversial. Our study compared morbidity and mortality between 1)diabetic and non-diabetic BIMA patients and 2)diabetic BIMA versus diabetic patients who underwent left internal mammary artery (LIMA) grafting only. Patients who underwent isolated CABG from July 2011 - June 2016 at any of the 10 centers in Maryland were propensity scored across 16 variables. Diabetic BIMA were matched 1:1 by nearest neighbor matching to non-diabetic BIMA patients, and were separately matched 1:1 to diabetic LIMA patients. We calculated observed to expected (O/E) ratios for composite morbidity/mortality, operative mortality, unplanned reoperation, stroke, renal failure, prolonged ventilation, and deep sternal wound infection) and compared ratios among matched populations. Over the study period, 812 CABG patients received BIMA grafts, including 302 patients (37%) with diabetes. We matched 259 diabetic and non-diabetic BIMA patients. O/E ratios were higher in matched diabetic (vs non-diabetic) BIMA patients when comparing composite morbidity/mortality, reoperation, stroke, renal failure, and prolonged ventilation (all O/E>1.0), however, O/E for operative mortality was higher in non-diabetic BIMA patients. We additionally matched 292 diabetic BIMA to diabetic LIMA patients. Diabetic BIMA patients had a higher O/E for composite morbidity/mortality, operative mortality, stroke, renal failure, and prolonged ventilation. In this statewide analysis, diabetics who received BIMA grafts (compared to diabetics with LIMA grafts or non-diabetics with BIMA grafts) had higher O/E ratios for composite morbidity/mortality as a result of higher O/E ratios for major complications. Copyright © 2018. Published by Elsevier Inc.

  8. Pericentriolar Targeting of the Mouse Mammary Tumor Virus GAG Protein.

    Directory of Open Access Journals (Sweden)

    Guangzhi Zhang

    Full Text Available The Gag protein of the mouse mammary tumor virus (MMTV is the chief determinant of subcellular targeting. Electron microscopy studies show that MMTV Gag forms capsids within the cytoplasm and assembles as immature particles with MMTV RNA and the Y box binding protein-1, required for centrosome maturation. Other betaretroviruses, such as Mason-Pfizer monkey retrovirus (M-PMV, assemble adjacent to the pericentriolar region because of a cytoplasmic targeting and retention signal in the Matrix protein. Previous studies suggest that the MMTV Matrix protein may also harbor a similar cytoplasmic targeting and retention signal. Herein, we show that a substantial fraction of MMTV Gag localizes to the pericentriolar region. This was observed in HEK293T, HeLa human cell lines and the mouse derived NMuMG mammary gland cells. Moreover, MMTV capsids were observed adjacent to centrioles when expressed from plasmids encoding either MMTV Gag alone, Gag-Pro-Pol or full-length virus. We found that the cytoplasmic targeting and retention signal in the MMTV Matrix protein was sufficient for pericentriolar targeting, whereas mutation of the glutamine to alanine at position 56 (D56/A resulted in plasma membrane localization, similar to previous observations from mutational studies of M-PMV Gag. Furthermore, transmission electron microscopy studies showed that MMTV capsids accumulate around centrioles suggesting that, similar to M-PMV, the pericentriolar region may be a site for MMTV assembly. Together, the data imply that MMTV Gag targets the pericentriolar region as a result of the MMTV cytoplasmic targeting and retention signal, possibly aided by the Y box protein-1 required for the assembly of centrosomal microtubules.

  9. Functional development of the adult ovine mammary gland--insights from gene expression profiling.

    Science.gov (United States)

    Paten, Amy M; Duncan, Elizabeth J; Pain, Sarah J; Peterson, Sam W; Kenyon, Paul R; Blair, Hugh T; Dearden, Peter K

    2015-10-05

    The mammary gland is a dynamic organ that undergoes dramatic physiological adaptations during the transition from late pregnancy to lactation. Investigation of the molecular basis of mammary development and function will provide fundamental insights into tissue remodelling as well as a better understanding of milk production and mammary disease. This is important to livestock production systems and human health. Here we use RNA-seq to identify differences in gene expression in the ovine mammary gland between late pregnancy and lactation. Between late pregnancy (135 days of gestation ± 2.4 SD) and lactation (15 days post partum ± 1.27 SD) 13 % of genes in the sheep genome were differentially expressed in the ovine mammary gland. In late pregnancy, cell proliferation, beta-oxidation of fatty acids and translation were identified as key biological processes. During lactation, high levels of milk fat synthesis were mirrored by enrichment of genes associated with fatty acid biosynthesis, transport and lipogenesis. Protein processing in the endoplasmic reticulum was enriched during lactation, likely in support of active milk protein synthesis. Hormone and growth factor signalling and activation of signal transduction pathways, including the JAK-STAT and PPAR pathways, were also differently regulated, indicating key roles for these pathways in functional development of the ovine mammary gland. Changes in the expression of epigenetic regulators, particularly chromatin remodellers, indicate a possible role in coordinating the large-scale transcriptional changes that appear to be required to switch mammary processes from growth and development during late pregnancy to synthesis and secretion of milk during lactation. Coordinated transcriptional regulation of large numbers of genes is required to switch between mammary tissue establishment during late pregnancy, and activation and maintenance of milk production during lactation. Our findings indicate the remarkable

  10. Focal Adhesion Kinase Is Required for Intestinal Regeneration and Tumorigenesis Downstream of Wnt/c-Myc Signaling

    Science.gov (United States)

    Ashton, Gabrielle H.; Morton, Jennifer P.; Myant, Kevin; Phesse, Toby J.; Ridgway, Rachel A.; Marsh, Victoria; Wilkins, Julie A.; Athineos, Dimitris; Muncan, Vanesa; Kemp, Richard; Neufeld, Kristi; Clevers, Hans; Brunton, Valerie; Winton, Douglas J.; Wang, Xiaoyan; Sears, Rosalie C.; Clarke, Alan R.; Frame, Margaret C.; Sansom, Owen J.

    2012-01-01

    SUMMARY The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration following DNA damage. Given Wnt/c-Myc signaling is activated following intestinal regeneration, we investigated the functional importance of FAK following deletion of the Apc tumor suppressor protein within the intestinal epithelium. Following Apc loss, FAK expression increased in a c-Myc-dependent manner. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Thus, FAK is required downstream of Wnt Signaling, for Akt/mTOR activation, intestinal regeneration, and tumorigenesis. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer. PMID:20708588

  11. Management of mastitis and abscessation of mammary glands secondary to fibroadenomatous hyperplasia in a primiparturient cat.

    Science.gov (United States)

    Burstyn, Uri

    2010-02-01

    A 1-year-old sexually intact female domestic shorthair cat was evaluated because of an 8-week history of pronounced mammary gland hyperplasia that had progressed to mastitis and abscessation of the mammary glands since parturition 7 days earlier. The cat was anorectic, was febrile, and had signs of discomfort. Its kittens were weak and appeared to have difficulty nursing. Physical examination revealed pyrexia, mastitis with abscessation in the 6 caudal mammary glands, skin ulceration over the nipples, and areas of skin necrosis over the abscessed mammary glands. A CBC revealed nonregenerative anemia and leukocytosis with a left shift (2.160 x 10(9) band cells/L) and toxic changes. Mastitis and incipient septicemia were considered the most likely causes. The history of mammary gland hyperplasia since the second week of pregnancy suggested a diagnosis of fibroadenomatous hyperplasia that predisposed the cat to subsequent mastitis. Surgical drainage of the abscessed mammary glands, debridement of necrotic skin, and placement of a Penrose drain resulted in rapid improvement in clinical status. Broad-spectrum antimicrobial treatment (amoxicillin-clavulanic acid) was prescribed, and the cat was discharged from the hospital. Mastitis and fibroadenomatous mammary gland hyperplasia resolved rapidly afterward. Management of abscessed mammary glands through surgical drainage and drain placement is an option for treatment of cats with complications of fibroadenomatous hyperplasia. In the cat of this report, the treatment approach resulted in rapid resolution of mastitis, was less invasive than mastectomy, and avoided the potential complications of treatment with a progesterone-receptor antagonist.

  12. Advanced Imaging Approaches to Characterize Stromal and Metabolic Changes in In Vivo Mammary Tumor Models

    Science.gov (United States)

    2015-02-01

    Bird , L. Yan, K. M. Vrotsos, K. W. Eliceiri, E. M. Vaughan, P. J. Keely, J. G. White, N. Ramanujam, Metabolic mapping of MCF10A human breast cells...1   Award Number: W81XWH-12-1-0025 TITLE: Advanced Imaging Approaches to Characterize Stromal and Metabolic Changes in In Vivo Mammary... Metabolic Changes in In Vivo Mammary Tumor Models 5b. GRANT NUMBER BC112240 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Betty Diamond 5d. PROJECT NUMBER

  13. Characterisation of microRNA expression in post-natal mouse mammary gland development

    Directory of Open Access Journals (Sweden)

    Karagavriilidou Konstantina

    2009-11-01

    Full Text Available Abstract Background The differential expression pattern of microRNAs (miRNAs during mammary gland development might provide insights into their role in regulating the homeostasis of the mammary epithelium. Our aim was to analyse these regulatory functions by deriving a comprehensive tissue-specific combined miRNA and mRNA expression profile of post-natal mouse mammary gland development. We measured the expression of 318 individual murine miRNAs by bead-based flow-cytometric profiling of whole mouse mammary glands throughout a 16-point developmental time course, including juvenile, puberty, mature virgin, gestation, lactation, and involution stages. In parallel whole-genome mRNA expression data were obtained. Results One third (n = 102 of all murine miRNAs analysed were detected during mammary gland development. MicroRNAs were represented in seven temporally co-expressed clusters, which were enriched for both miRNAs belonging to the same family and breast cancer-associated miRNAs. Global miRNA and mRNA expression was significantly reduced during lactation and the early stages of involution after weaning. For most detected miRNA families we did not observe systematic changes in the expression of predicted targets. For miRNA families whose targets did show changes, we observed inverse patterns of miRNA and target expression. The data sets are made publicly available and the combined expression profiles represent an important community resource for mammary gland biology research. Conclusion MicroRNAs were expressed in likely co-regulated clusters during mammary gland development. Breast cancer-associated miRNAs were significantly enriched in these clusters. The mechanism and functional consequences of this miRNA co-regulation provide new avenues for research into mammary gland biology and generate candidates for functional validation.

  14. Inhibition of Staphylococcus aureus Invasion into Bovine Mammary Epithelial Cells by Contact with Live Lactobacillus casei